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Shaw P, Dey Bhowmik A, Gopinatha Pillai MS, Robbins N, Dwivedi SKD, Rao G. Anoikis resistance in Cancer: Mechanisms, therapeutic strategies, potential targets, and models for enhanced understanding. Cancer Lett 2025; 624:217750. [PMID: 40294841 DOI: 10.1016/j.canlet.2025.217750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 04/01/2025] [Accepted: 04/26/2025] [Indexed: 04/30/2025]
Abstract
Anoikis, defined as programmed cell death triggered by the loss of cell-extracellular matrix (ECM) and cell-cell interactions, is crucial for maintaining tissue homeostasis and preventing aberrant cell migration. Cancer cells, however, display anoikis resistance (AR) which in turn enables cancer metastasis. AR results from alterations in apoptotic signaling, metabolic reprogramming, autophagy modulation, and epigenetic changes, allowing cancer cells to survive in detached conditions. In this review we describe the mechanisms underlying both anoikis and AR, focusing on intrinsic and extrinsic pathways, disrupted cell-ECM interactions, and autophagy in cancer. Recent findings (i.e., between 2014 and 2024) on epigenetic regulation of AR and its role in metastasis are discussed. Therapeutic strategies targeting AR, including chemical inhibitors, are highlighted alongside a network analysis of 122 proteins reported to be associated with AR which identifies 53 hub proteins as potential targets. We also evaluate in vitro and in vivo models for studying AR, emphasizing their role in advancing metastasis research. Our overall goal is to guide future studies and therapeutic developments to counter cancer metastasis.
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Affiliation(s)
- Pallab Shaw
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Arpan Dey Bhowmik
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Mohan Shankar Gopinatha Pillai
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Nathan Robbins
- James E. Hurley School of Science and Mathematics, Oklahoma Baptist University, Shawnee, OK, USA
| | - Shailendra Kumar Dhar Dwivedi
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA
| | - Geeta Rao
- Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA; Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, 73104, Oklahoma, USA.
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Abdulrahman FA, Benford KA, Lin GT, Maroun AJ, Sammons C, Shirzad DN, Tsai H, Van Brunt VL, Jones Z, Marquez JE, Ratkus EC, Shehadeh AK, Abasto Valle H, Fejzo D, Gilbert AE, McWee CA, Underwood LF, Indico E, Rork BB, Nanjundan M. zDHHC-Mediated S-Palmitoylation in Skin Health and Its Targeting as a Treatment Perspective. Int J Mol Sci 2025; 26:1673. [PMID: 40004137 PMCID: PMC11854935 DOI: 10.3390/ijms26041673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
S-acylation, which includes S-palmitoylation, is the only known reversible lipid-based post-translational protein modification. S-palmitoylation is mediated by palmitoyl acyltransferases (PATs), a family of 23 enzymes commonly referred to as zDHHCs, which catalyze the addition of palmitate to cysteine residues on specific target proteins. Aberrant S-palmitoylation events have been linked to the pathogenesis of multiple human diseases. While there have been advances in elucidating the molecular mechanisms underlying the pathogenesis of various skin conditions, there remain gaps in the knowledge, specifically with respect to the contribution of S-palmitoylation to the maintenance of skin barrier function. Towards this goal, we performed PubMed literature searches relevant to S-palmitoylation in skin to define current knowledge and areas that may benefit from further research studies. Furthermore, to identify alterations in gene products that are S-palmitoylated, we utilized bioinformatic tools such as SwissPalm and analyzed relevant data from publicly available databases such as cBioportal. Since the targeting of S-palmitoylated targets may offer an innovative treatment perspective, we surveyed small molecules inhibiting zDHHCs, including 2-bromopalmitate (2-BP) which is associated with off-target effects, and other targeting strategies. Collectively, our work aims to advance both basic and clinical research on skin barrier function with a focus on zDHHCs and relevant protein targets that may contribute to the pathogenesis of skin conditions such as atopic dermatitis, psoriasis, and skin cancers including melanoma.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Meera Nanjundan
- Department of Molecular Biosciences, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa, FL 33620, USA; (F.A.A.); (K.A.B.); (G.T.L.); (A.J.M.); (C.S.); (D.N.S.); (H.T.); (V.L.V.B.); (Z.J.); (J.E.M.); (E.C.R.); (A.K.S.); (H.A.V.); (D.F.); (A.E.G.); (C.A.M.); (L.F.U.); (E.I.); (B.B.R.)
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Chen YL, Chu CA, Wang JY, Chen WL, Wang YW, Ho CL, Lee CT, Chow NH. Nuclear translocation of RON receptor tyrosine kinase. New mechanistic and functional insights. Cytokine Growth Factor Rev 2025; 81:9-15. [PMID: 39794156 DOI: 10.1016/j.cytogfr.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 12/26/2024] [Indexed: 01/13/2025]
Abstract
Receptor tyrosine kinases (RTKs) are membrane sensors that monitor alterations in the extracellular milieu and translate this information into appropriate cellular responses. Epidermal growth factor receptor (EGFR) is the most well-known model in which gene expression is upregulated by mitogenic signals through the activation of multiple signaling cascades or by nuclear translocation of the full-length EGFR protein. RON (Receptuer d'Origine Nantatise, also known as macrophage stimulating 1 receptor, MST1R) has recently gained attention as a therapeutic target for human cancer. This review summarizes the recent understanding of the unusual nuclear translocation of uncleaved RON receptor proteins in response to cellular stresses, such as serum starvation, hormonal deprivation, hypoxia, and genotoxicity. This nonligand mechanism, achieved by RON per se or by interaction with EGFR, may directly activate the transcriptional machinery necessary for cancer cells to survive. In vitro experiments have demonstrated the importance of tyrosine kinase of RON in binding to and activating the c-JUN promoter, HIF-1α, DNA helicase 2, DNA-dependent protein kinase catalytic subunit, and other stress-responsive networks. Nuclear RON-activated nonhomologous end joining repair confers chemoresistance to drugs that induce double-strand breaks (DSBs) in cancer cells. Tyrosine kinase inhibitors or monoclonal antibodies targeting RON kinase may therefore be useful treatments for patients with RON-overexpressing tumors. DSB-inducing anticancer drugs are not recommended for these cancer patients. Moreover, multi-RTK inhibition is a more rational strategy for patients with RON- and RTK-coexpressing human cancer.
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Affiliation(s)
- Yi-Lin Chen
- Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Chien-An Chu
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Jiu-Yao Wang
- Center for Allergy, Immunology, and Microbiome (A.I.M.), China Medical University Hospital, Taichung, Taiwan; Department of Allergy, Immunology, and Rheumatology (AIR), China Medical University Children's Hospital, Taichung, Taiwan
| | - Wan-Li Chen
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Yi-Wen Wang
- Department of Food Safety Hygiene and Risk Management, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Liang Ho
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chung-Ta Lee
- Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Pathology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Nan-Haw Chow
- Center for Precision Medicine, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Pathology, College of Medicine, China Medical University, Taichung, Taiwan.
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Yousefi R, Cruz-Zaragoza LD, Valpadashi A, Hansohn C, Dahal D, Richter-Dennerlein R, Rizzoli S, Urlaub H, Rehling P, Pacheu-Grau D. A microscopy-based screen identifies cellular kinases modulating mitochondrial translation. Cell Rep 2025; 44:115143. [PMID: 39932185 DOI: 10.1016/j.celrep.2024.115143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 11/10/2024] [Accepted: 12/12/2024] [Indexed: 05/02/2025] Open
Abstract
Mitochondrial DNA encodes 13 subunits of the oxidative phosphorylation (OXPHOS) system, which are synthesized inside the organelle and essential for cellular energy supply. How mitochondrial gene expression is regulated and integrated into cellular physiology is little understood. Here, we perform a high-throughput screen combining fluorescent labeling of mitochondrial translation products with small interfering RNA (siRNA)-mediated knockdown to identify cellular kinases regulating translation. As proof of principle, the screen identifies known kinases that affect mitochondrial translation, and it also reveals several kinases not yet linked to this process. Among the latter, we focus on the primarily cytosolic kinase, fructosamine 3 kinase (FN3K), which localizes partially to the mitochondria to support translation. FN3K interacts with the mitochondrial ribosome and modulates its assembly, thereby affecting translation. Overall, our work provides a reliable approach to identify protein functions for mitochondrial gene expression in a high-throughput manner.
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Affiliation(s)
- Roya Yousefi
- Department of Cellular Biochemistry, University Medical Center Göttingen, 37073 Göttingen, Germany
| | | | - Anusha Valpadashi
- Department of Cellular Biochemistry, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Carina Hansohn
- Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany; Institute for Clinical Chemistry, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Drishan Dahal
- Department of Cellular Biochemistry, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Ricarda Richter-Dennerlein
- Department of Cellular Biochemistry, University Medical Center Göttingen, 37073 Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, 37075 Göttingen, Germany
| | - Silvio Rizzoli
- Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, 37075 Göttingen, Germany; Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Henning Urlaub
- Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, 37075 Göttingen, Germany; Institute for Clinical Chemistry, University Medical Center Göttingen, 37073 Göttingen, Germany
| | - Peter Rehling
- Department of Cellular Biochemistry, University Medical Center Göttingen, 37073 Göttingen, Germany; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, 37075 Göttingen, Germany; Max Planck Institute for Multidisciplinary Science, 37077 Göttingen, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Translational Neuroinflammation and Automated Microscopy, 37073 Göttingen, Germany.
| | - David Pacheu-Grau
- Department of Cellular Biochemistry, University Medical Center Göttingen, 37073 Göttingen, Germany; Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, 50009/50013 Zaragoza, Spain; Instituto de Investigación Sanitaria (IIS) de Aragón, 50009 Zaragoza, Spain; Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain
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Pham L, Arroum T, Wan J, Pavelich L, Bell J, Morse PT, Lee I, Grossman LI, Sanderson TH, Malek MH, Hüttemann M. Regulation of mitochondrial oxidative phosphorylation through tight control of cytochrome c oxidase in health and disease - Implications for ischemia/reperfusion injury, inflammatory diseases, diabetes, and cancer. Redox Biol 2024; 78:103426. [PMID: 39566165 PMCID: PMC11617887 DOI: 10.1016/j.redox.2024.103426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/04/2024] [Accepted: 11/09/2024] [Indexed: 11/22/2024] Open
Abstract
Mitochondria are essential to cellular function as they generate the majority of cellular ATP, mediated through oxidative phosphorylation, which couples proton pumping of the electron transport chain (ETC) to ATP production. The ETC generates an electrochemical gradient, known as the proton motive force, consisting of the mitochondrial membrane potential (ΔΨm, the major component in mammals) and ΔpH across the inner mitochondrial membrane. Both ATP production and reactive oxygen species (ROS) are linked to ΔΨm, and it has been shown that an imbalance in ΔΨm beyond the physiological optimal intermediate range results in excessive ROS production. The reaction of cytochrome c oxidase (COX) of the ETC with its small electron donor cytochrome c (Cytc) is the proposed rate-limiting step in mammals under physiological conditions. The rate at which this redox reaction occurs controls ΔΨm and thus ATP and ROS production. Multiple mechanisms are in place that regulate this reaction to meet the cell's energy demand and respond to acute stress. COX and Cytc have been shown to be regulated by all three main mechanisms, which we discuss in detail: allosteric regulation, tissue-specific isoforms, and post-translational modifications for which we provide a comprehensive catalog and discussion of their functional role with 55 and 50 identified phosphorylation and acetylation sites on COX, respectively. Disruption of these regulatory mechanisms has been found in several common human diseases, including stroke and myocardial infarction, inflammation including sepsis, and diabetes, where changes in COX or Cytc phosphorylation lead to mitochondrial dysfunction contributing to disease pathophysiology. Identification and subsequent targeting of the underlying signaling pathways holds clear promise for future interventions to improve human health. An example intervention is the recently discovered noninvasive COX-inhibitory infrared light therapy that holds promise to transform the current standard of clinical care in disease conditions where COX regulation has gone awry.
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Affiliation(s)
- Lucynda Pham
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Tasnim Arroum
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Junmei Wan
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Lauren Pavelich
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA.
| | - Jamie Bell
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA; Division of Pediatric Critical Care, Children's Hospital of Michigan, Central Michigan University, Detroit, MI, 48201, USA.
| | - Paul T Morse
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Icksoo Lee
- College of Medicine, Dankook University, Cheonan-si, 31116, Republic of Korea.
| | - Lawrence I Grossman
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA.
| | - Thomas H Sanderson
- Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
| | - Moh H Malek
- Department of Health Care Sciences, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, MI, 48201, USA.
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, 48201, USA; Department of Biochemistry, Microbiology, and Immunology, Wayne State University, Detroit, MI, 48201, USA.
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Zhu J, Wu Z, Shan G, Huang Y, Liang J, Zhan C. Nuclear epidermal growth factor receptor (nEGFR) in clinical treatment. Heliyon 2024; 10:e40150. [PMID: 39568844 PMCID: PMC11577184 DOI: 10.1016/j.heliyon.2024.e40150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/03/2024] [Accepted: 11/04/2024] [Indexed: 11/22/2024] Open
Abstract
The epidermal growth factor receptor (EGFR) is a recognized target in tumor treatment. While there is significant focus on inhibiting membrane EGFR and its downstream signaling activation, the ectopic accumulation of EGFR, particularly nuclear EGFR (nEGFR), has been implicated in tumor-associated activities and associated with poor prognosis. Within the nucleus, nEGFR functions as a transcriptional regulator to modulate transcriptional landscape and exerts tyrosine kinase activity to phosphorylate nuclear proteins and subsequently influences DNA repair, cell cycle, proliferation, and resistance to radiotherapy and chemotherapy. The nuclear localization of EGFR involves the internalization, subcellular trafficking, and nuclear envelope shuttling of membrane EGFR. Given the challenges of delivering drugs to the nucleus for targeting nEGFR, understanding the molecules affecting the translocation process is crucial for novel insights. This review initially explores the association between nEGFR expression and clinical outcomes and then elucidates how nEGFR fulfills its regulatory role within the nucleus. Subsequently, the mechanisms governing EGFR nuclear translocation and potential therapeutic targets during this process are summarized, highlighting avenues to target nEGFR as an innovative strategy in tumor treatment.
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Affiliation(s)
- Junkan Zhu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China
| | - Zhiyao Wu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China
| | - Guangyao Shan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China
| | - Yiwei Huang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China
| | - Jiaqi Liang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China
| | - Cheng Zhan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Xuhui District, Shanghai, 200032, China
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Wei C, Peng D, Jing B, Wang B, Li Z, Yu R, Zhang S, Cai J, Zhang Z, Zhang J, Han L. A novel protein SPECC1-415aa encoded by N6-methyladenosine modified circSPECC1 regulates the sensitivity of glioblastoma to TMZ. Cell Mol Biol Lett 2024; 29:127. [PMID: 39333871 PMCID: PMC11429730 DOI: 10.1186/s11658-024-00644-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) can influence a variety of biological functions and act as a significant role in the progression and recurrence of glioblastoma (GBM). However, few coding circRNAs have been discovered in cancer, and their role in GBM is still unknown. The aim of this study was to identify coding circRNAs and explore their potential roles in the progression and recurrence of GBM. METHODS CircSPECC1 was screened via circRNAs microarray of primary and recurrent GBM samples. To ascertain the characteristics and coding ability of circSPECC1, we conducted a number of experiments. Afterward, through in vivo and in vitro experiments, we investigated the biological functions of circSPECC1 and its encoded novel protein (SPECC1-415aa) in GBM, as well as their effects on TMZ sensitivity. RESULTS By analyzing primary and recurrent GBM samples via circRNAs microarray, circSPECC1 was found to be a downregulated circRNA with coding potential in recurrent GBM compared with primary GBM. CircSPECC1 suppressed the proliferation, migration, invasion, and colony formation abilities of GBM cells by encoding a new protein known as SPECC1-415aa. CircSPECC1 restored TMZ sensitivity in TMZ-resistant GBM cells by encoding the new protein SPECC1-415aa. The m6A reader protein IGF2BP1 can bind to circSPECC1 to promote its expression and stability. Mechanistically, SPECC1-415aa can bind to ANXA2 and competitively inhibit the binding of ANXA2 to EGFR, thus resulting in the inhibition of the phosphorylation of EGFR (Tyr845) and its downstream pathway protein AKT (Ser473). In vivo experiments showed that the overexpression of circSPECC1 could combine with TMZ to treat TMZ-resistant GBM, thereby restoring the sensitivity of TMZ-resistant GBM to TMZ. CONCLUSIONS CircSPECC1 was downregulated in recurrent GBM compared with primary GBM. The m6A reader protein IGF2BP1 could promote the expression and stability of circSPECC1. The sequence of SPECC1-415aa, which is encoded by circSPECC1, can inhibit the binding of ANXA2 to EGFR by competitively binding to ANXA2 and inhibiting the phosphorylation of EGFR and AKT, thereby restoring the sensitivity of TMZ-resistant GBM cells to TMZ.
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Affiliation(s)
- Cheng Wei
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Dazhao Peng
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Boyuan Jing
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Bo Wang
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Zesheng Li
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Runze Yu
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Shu Zhang
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China
| | - Jinquan Cai
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Nangang District, Harbin, 150086, China.
| | - Zhenyu Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Jian She Dong Road 1, Zhengzhou, 480082, Henan Province, China.
| | - Jianning Zhang
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
| | - Lei Han
- Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, China.
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Rodriguez NR, Fortune T, Hegde E, Weinstein MP, Keane AM, Mangold JF, Swartz TH. Oxidative phosphorylation in HIV-1 infection: impacts on cellular metabolism and immune function. Front Immunol 2024; 15:1360342. [PMID: 38529284 PMCID: PMC10962326 DOI: 10.3389/fimmu.2024.1360342] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 02/26/2024] [Indexed: 03/27/2024] Open
Abstract
Human Immunodeficiency Virus Type 1 (HIV-1) presents significant challenges to the immune system, predominantly characterized by CD4+ T cell depletion, leading to Acquired Immunodeficiency Syndrome (AIDS). Antiretroviral therapy (ART) effectively suppresses the viral load in people with HIV (PWH), leading to a state of chronic infection that is associated with inflammation. This review explores the complex relationship between oxidative phosphorylation, a crucial metabolic pathway for cellular energy production, and HIV-1, emphasizing the dual impact of HIV-1 infection and the metabolic and mitochondrial effects of ART. The review highlights how HIV-1 infection disrupts oxidative phosphorylation, promoting glycolysis and fatty acid synthesis to facilitate viral replication. ART can exacerbate metabolic dysregulation despite controlling viral replication, impacting mitochondrial DNA synthesis and enhancing reactive oxygen species production. These effects collectively contribute to significant changes in oxidative phosphorylation, influencing immune cell metabolism and function. Adenosine triphosphate (ATP) generated through oxidative phosphorylation can influence the metabolic landscape of infected cells through ATP-detected purinergic signaling and contributes to immunometabolic dysfunction. Future research should focus on identifying specific targets within this pathway and exploring the role of purinergic signaling in HIV-1 pathogenesis to enhance HIV-1 treatment modalities, addressing both viral infection and its metabolic consequences.
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Affiliation(s)
| | | | | | | | | | | | - Talia H. Swartz
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Leung PY, Chen W, Sari AN, Sitaram P, Wu PK, Tsai S, Park JI. Erlotinib combination with a mitochondria-targeted ubiquinone effectively suppresses pancreatic cancer cell survival. World J Gastroenterol 2024; 30:714-727. [PMID: 38515951 PMCID: PMC10950623 DOI: 10.3748/wjg.v30.i7.714] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/13/2023] [Accepted: 01/17/2024] [Indexed: 02/21/2024] Open
Abstract
BACKGROUND Pancreatic cancer is a leading cause of cancer-related deaths. Increased activity of the epidermal growth factor receptor (EGFR) is often observed in pancreatic cancer, and the small molecule EGFR inhibitor erlotinib has been approved for pancreatic cancer therapy by the food and drug administration. Nevertheless, erlotinib alone is ineffective and should be combined with other drugs to improve therapeutic outcomes. We previously showed that certain receptor tyrosine kinase inhibitors can increase mitochondrial membrane potential (Δψm), facilitate tumor cell uptake of Δψm-sensitive agents, disrupt mitochondrial homeostasis, and subsequently trigger tumor cell death. Erlotinib has not been tested for this effect. AIM To determine whether erlotinib can elevate Δψm and increase tumor cell uptake of Δψm-sensitive agents, subsequently triggering tumor cell death. METHODS Δψm-sensitive fluorescent dye was used to determine how erlotinib affects Δψm in pancreatic adenocarcinoma (PDAC) cell lines. The viability of conventional and patient-derived primary PDAC cell lines in 2D- and 3D cultures was measured after treating cells sequentially with erlotinib and mitochondria-targeted ubiquinone (MitoQ), a Δψm-sensitive MitoQ. The synergy between erlotinib and MitoQ was then analyzed using SynergyFinder 2.0. The preclinical efficacy of the two-drug combination was determined using immune-compromised nude mice bearing PDAC cell line xenografts. RESULTS Erlotinib elevated Δψm in PDAC cells, facilitating tumor cell uptake and mitochondrial enrichment of Δψm-sensitive agents. MitoQ triggered caspase-dependent apoptosis in PDAC cells in culture if used at high doses, while erlotinib pretreatment potentiated low doses of MitoQ. SynergyFinder suggested that these drugs synergistically induced tumor cell lethality. Consistent with in vitro data, erlotinib and MitoQ combination suppressed human PDAC cell line xenografts in mice more effectively than single treatments of each agent. CONCLUSION Our findings suggest that a combination of erlotinib and MitoQ has the potential to suppress pancreatic tumor cell viability effectively.
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Affiliation(s)
- Pui-Yin Leung
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Wenjing Chen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Anissa N Sari
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Poojitha Sitaram
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Pui-Kei Wu
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Susan Tsai
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, United States
| | - Jong-In Park
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, United States
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10
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Pergu R, Shoba VM, Chaudhary SK, Munkanatta Godage DNP, Deb A, Singha S, Dhawa U, Singh P, Anokhina V, Singh S, Siriwardena SU, Choudhary A. Development and Applications of Chimera Platforms for Tyrosine Phosphorylation. ACS CENTRAL SCIENCE 2023; 9:1558-1566. [PMID: 37637727 PMCID: PMC10450875 DOI: 10.1021/acscentsci.3c00200] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Indexed: 08/29/2023]
Abstract
Chimeric small molecules that induce post-translational modification (PTM) on a target protein by bringing it into proximity to a PTM-inducing enzyme are furnishing novel modalities to perturb protein function. Despite recent advances, such molecules are unavailable for a critical PTM, tyrosine phosphorylation. Furthermore, the contemporary design paradigm of chimeric molecules, formed by joining a noninhibitory binder of the PTM-inducing enzyme with the binder of the target protein, prohibits the recruitment of most PTM-inducing enzymes as their noninhibitory binders are unavailable. Here, we report two platforms to generate phosphorylation-inducing chimeric small molecules (PHICS) for tyrosine phosphorylation. We generate PHICS from both noninhibitory binders (scantily available, platform 1) and kinase inhibitors (abundantly available, platform 2) using cysteine-based group transfer chemistry. PHICS triggered phosphorylation on tyrosine residues in diverse sequence contexts and target proteins (e.g., membrane-associated, cytosolic) and displayed multiple bioactivities, including the initiation of a growth receptor signaling cascade and the death of drug-resistant cancer cells. These studies provide an approach to induce biologically relevant PTM and lay the foundation for pharmacologic PTM editing (i.e., induction or removal) of target proteins using abundantly available inhibitors of PTM-inducing or -erasing enzymes.
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Affiliation(s)
- Rajaiah Pergu
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Veronika M. Shoba
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Santosh K. Chaudhary
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | | | - Arghya Deb
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Santanu Singha
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Uttam Dhawa
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Prashant Singh
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Viktoriya Anokhina
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Sameek Singh
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Sachini U. Siriwardena
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Amit Choudhary
- Chemical
Biology and Therapeutics Science, Broad
Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
- Department
of Medicine, Harvard Medical School, Boston, Massachusetts 02115, United States
- Divisions
of Renal Medicine and Engineering, Brigham
and Women’s Hospital, Boston, Massachusetts 02115, United States
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11
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Dai Y, Zhang X, Ou Y, Zou L, Zhang D, Yang Q, Qin Y, Du X, Li W, Yuan Z, Xiao Z, Wen Q. Anoikis resistance--protagonists of breast cancer cells survive and metastasize after ECM detachment. Cell Commun Signal 2023; 21:190. [PMID: 37537585 PMCID: PMC10399053 DOI: 10.1186/s12964-023-01183-4] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 06/04/2023] [Indexed: 08/05/2023] Open
Abstract
Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.
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Affiliation(s)
- Yalan Dai
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Department of Oncology, Garze Tibetan Autonomous Prefecture People's Hospital, Kangding, China
| | - Xinyi Zhang
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shenzhen, China
| | - Yingjun Ou
- Clinical Medicine School, Southwest Medicial Univercity, Luzhou, China
- Orthopaedics, Garze Tibetan Autonomous Prefecture People's Hospital, Kangding, China
| | - Linglin Zou
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Duoli Zhang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qingfan Yang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yi Qin
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Xiuju Du
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Wei Li
- Southwest Medical University, Luzhou, China
| | | | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China.
| | - Qinglian Wen
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
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12
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Yuan SSF, Wang YM, Chan LP, Hung AC, Nguyen HDH, Chen YK, Hu SCS, Lo S, Wang YY. IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway. J Transl Med 2023; 21:473. [PMID: 37461111 PMCID: PMC10351194 DOI: 10.1186/s12967-023-04343-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 07/10/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND Interleukin-1 receptor antagonist (IL-1RA), a member of the IL-1 family, has diverse roles in cancer development. However, the role of IL-1RA in oral squamous cell carcinoma (OSCC), in particular the underlying mechanisms, remains to be elucidated. METHODS Tumor tissues from OSCC patients were assessed for protein expression by immunohistochemistry. Patient survival was evaluated by Kaplan-Meier curve analysis. Impact of differential IL-1RA expression on cultured OSCC cell lines was assessed in vitro by clonogenic survival, tumorsphere formation, soft agar colony formation, and transwell cell migration and invasion assays. Oxygen consumption rate was measured by Seahorse analyzer or multi-mode plate reader. PCR array was applied to screen human cancer stem cell-related genes, proteome array for phosphorylation status of kinases, and Western blot for protein expression in cultured cells. In vivo tumor growth was investigated by orthotopic xenograft in mice, and protein expression in xenograft tumors assessed by immunohistochemistry. RESULTS Clinical analysis revealed that elevated IL-1RA expression in OSCC tumor tissues was associated with increased tumor size and cancer stage, and reduced survival in the patient group receiving adjuvant radiotherapy compared to the patient group without adjuvant radiotherapy. In vitro data supported these observations, showing that overexpression of IL-1RA increased OSCC cell growth, migration/invasion abilities, and resistance to ionizing radiation, whereas knockdown of IL-1RA had largely the opposite effects. Additionally, we identified that EGFR/JNK activation and SOX2 expression were modulated by differential IL-1RA expression downstream of mitochondrial metabolism, with application of mitochondrial complex inhibitors suppressing these pathways. Furthermore, in vivo data revealed that treatment with cisplatin or metformin-a mitochondrial complex inhibitor and conventional therapy for type 2 diabetes-reduced IL-1RA-associated xenograft tumor growth as well as EGFR/JNK activation and SOX2 expression. This inhibitory effect was further augmented by combination treatment with cisplatin and metformin. CONCLUSIONS The current study suggests that IL-1RA promoted OSCC malignancy through mitochondrial metabolism-mediated EGFR/JNK activation and SOX2 expression. Inhibition of this mitochondrial metabolic pathway may present a potential therapeutic strategy in OSCC.
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Affiliation(s)
- Shyng-Shiou F Yuan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300, Taiwan
| | - Yun-Ming Wang
- Department of Biological Science and Technology, Institute of Molecular Medicine and Bioengineering, Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, 75 Bo-Ai Street, Hsinchu, 300, Taiwan
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1St Road, Sanmin Dist., Kaohsiung, 80708, Taiwan
| | - Leong-Perng Chan
- Cohort Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Otorhinolaryngology-Head and Neck Surgery, Kaohsiung Municipal Ta-Tung Hospital and Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Amos C Hung
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Hieu D H Nguyen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1St Road, Sanmin Dist., Kaohsiung, 80708, Taiwan
| | - Yuk-Kwan Chen
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1St Road, Sanmin Dist., Kaohsiung, 80708, Taiwan
- Division of Oral Pathology & Maxillofacial Radiology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Stephen Chu-Sung Hu
- Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Steven Lo
- Canniesburn Regional Plastic Surgery and Burns Unit, Glasgow, G4 0SF, UK
- College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Yen-Yun Wang
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan.
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, No.100, Shih-Chuan 1St Road, Sanmin Dist., Kaohsiung, 80708, Taiwan.
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13
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Luo L, Wei D, Pan Y, Wang QX, Feng JX, Yu B, Kang T, Luo J, Yang J, Gao S. MFN2 suppresses clear cell renal cell carcinoma progression by modulating mitochondria-dependent dephosphorylation of EGFR. Cancer Commun (Lond) 2023. [PMID: 37378422 PMCID: PMC10354417 DOI: 10.1002/cac2.12428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Clear cell renal cell carcinoma (ccRCC) is the most lethal renal cancer. An overwhelming increase of patients experience tumor progression and unfavorable prognosis. However, the molecular events underlying ccRCC tumorigenesis and metastasis remain unclear. Therefore, uncovering the underlying mechanisms will pave the way for developing novel therapeutic targets for ccRCC. In this study, we sought to investigate the role of mitofusin-2 (MFN2) in supressing ccRCC tumorigenesis and metastasis. METHODS The expression pattern and clinical significance of MFN2 in ccRCC were analyzed by using the Cancer Genome Atlas datasets and samples from our independent ccRCC cohort. Both in vitro and in vivo experiments, including cell proliferation, xenograft mouse models and transgenic mouse model, were used to determine the role of MFN2 in regulating the malignant behaviors of ccRCC. RNA-sequencing, mass spectrum analysis, co-immunoprecipitation, bio-layer interferometry and immunofluorescence were employed to elucidate the molecular mechanisms for the tumor-supressing role of MFN2. RESULTS we reported a tumor-suppressing pathway in ccRCC, characterized by mitochondria-dependent inactivation of epidermal growth factor receptor (EGFR) signaling. This process was mediated by the outer mitochondrial membrane (OMM) protein MFN2. MFN2 was down-regulated in ccRCC and associated with favorable prognosis of ccRCC patients. in vivo and in vitro assays demonstrated that MFN2 inhibited ccRCC tumor growth and metastasis by suppressing the EGFR signaling pathway. In a kidney-specific knockout mouse model, loss of MFN2 led to EGFR pathway activation and malignant lesions in kidney. Mechanistically, MFN2 preferably binded small GTPase Rab21 in its GTP-loading form, which was colocalized with endocytosed EGFR in ccRCC cells. Through this EGFR-Rab21-MFN2 interaction, endocytosed EGFR was docked to mitochondria and subsequently dephosphorylated by the OMM-residing tyrosine-protein phosphatase receptor type J (PTPRJ). CONCLUSIONS Our findings uncover an important non-canonical mitochondria-dependent pathway regulating EGFR signaling by the Rab21-MFN2-PTPRJ axis, which contributes to the development of novel therapeutic strategies for ccRCC.
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Affiliation(s)
- Li Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Denghui Wei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Yihui Pan
- Department of Urology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, P. R. China
| | - Qiu-Xia Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Jian-Xiong Feng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Bing Yu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Tiebang Kang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
| | - Junhang Luo
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jiefeng Yang
- Department of Urology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Song Gao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, P. R. China
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14
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Mani I, Singh V. An overview of receptor endocytosis and signaling. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 194:1-18. [PMID: 36631188 DOI: 10.1016/bs.pmbts.2022.06.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Endocytosis is a cellular process which mediates receptor internalization, nutrient uptake, and the regulation of cell signaling. Microorganisms (many bacteria and viruses) and toxins also use the same process and enter the cells. Generally, endocytosis is considered in the three forms such as phagocytosis (cell eating), pinocytosis (cell drinking), and highly selective receptor-mediated endocytosis (clathrin-dependent and independent). Several endocytic routes exist in an analogous, achieving diverse functions. Most studies on endocytosis have used transformed cells in culture. To visualize the receptor internalization, trafficking, and signaling in subcellular organelles, a green fluorescent protein-tagged receptor has been utilized. It also helps to visualize the endocytosis effects in live-cell imaging. Confocal laser microscopy increases our understanding of receptor endocytosis and signaling. Site-directed mutagenesis studies demonstrated that many short-sequence motifs of the cytoplasmic domain of receptors significantly play a vital role in receptor internalization, subcellular trafficking, and signaling. However, other factors also regulate receptor internalization through clathrin-coated vesicles. Receptor endocytosis can occur through clathrin-dependent and clathrin-independent pathways. This chapter briefly discusses the internalization, trafficking, and signaling of various receptors in normal conditions. In addition, it also highlights the malfunction of the receptor in disease conditions.
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Affiliation(s)
- Indra Mani
- Department of Microbiology, Gargi College, University of Delhi, New Delhi, India.
| | - Vijai Singh
- Department of Biosciences, School of Science, Indrashil University, Rajpur, Mehsana, Gujarat, India
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15
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Pagano C, Coppola L, Navarra G, Avilia G, Bruzzaniti S, Piemonte E, Galgani M, Della Monica R, Chiariotti L, Cuomo M, Buonaiuto M, Torelli G, Caiazzo P, Laezza C, Bifulco M. N6-Isopentenyladenosine Impairs Mitochondrial Metabolism through Inhibition of EGFR Translocation on Mitochondria in Glioblastoma Cells. Cancers (Basel) 2022; 14:cancers14246044. [PMID: 36551529 PMCID: PMC9776489 DOI: 10.3390/cancers14246044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/30/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is poorly susceptible to cytotoxic therapies. Amplification of the epidermal growth factor receptor (EGFR) and deletion of exons 2 to 7, which generates EGFR variant III (vIII), are the most common molecular alterations of GBMs that contribute to the aggressiveness of the disease. Recently, it has been shown that EGFR/EGFRvIII-targeted inhibitors enhance mitochondrial translocation by causing mitochondrial accumulation of these receptors, promoting the tumor drug resistance; moreover, they negatively modulate intrinsic mitochondria-mediated apoptosis by sequestering PUMA, leading to impaired apoptotic response in GBM cells. N6-isopentenyladenosine (i6A or iPA), a cytokinin consisting of an adenosine linked to an isopentenyl group deriving from the mevalonate pathway, has antiproliferative effects on numerous tumor cells, including GBM cells, by inducing cell death in vitro and in vivo. Here, we observed that iPA inhibits the mitochondrial respiration in GBM cells by preventing the translocation of EGFR/EGFRvIII to the mitochondria and allowing PUMA to interact with them by promoting changes in mitochondrial activity, thus playing a critical role in cell death. Our findings clearly demonstrate that iPA interferes with mitochondrial bioenergetic capacity, providing a rationale for an effective strategy for treating GBM.
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Affiliation(s)
- Cristina Pagano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Laura Coppola
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Giovanna Navarra
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Giorgio Avilia
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Sara Bruzzaniti
- Department of Biology, University of Naples “Federico II”, 80126 Naples, Italy
- Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), 80125 Naples, Italy
| | - Erica Piemonte
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Mario Galgani
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
- Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), 80125 Naples, Italy
| | - Rosa Della Monica
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
- CEINGE—Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80131 Naples, Italy
| | - Lorenzo Chiariotti
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
- CEINGE—Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80131 Naples, Italy
| | - Mariella Cuomo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
- CEINGE—Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80131 Naples, Italy
| | - Michela Buonaiuto
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
- CEINGE—Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80131 Naples, Italy
| | - Giovanni Torelli
- Neurosurgery Unit A.O. San Giovanni di Dio e Ruggi d’ Aragona, Salerno’s School of Medicine Largo Città di Ippocrate, 84131 Salerno, Italy
- Osservatorio Oncologico, 84091 Battipaglia, Italy
| | | | - Chiara Laezza
- Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), 80125 Naples, Italy
- Correspondence: or (C.L.); (M.B.)
| | - Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy
- Correspondence: or (C.L.); (M.B.)
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16
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Min JK, Park HS, Lee YB, Kim JG, Kim JI, Park JB. Cross-Talk between Wnt Signaling and Src Tyrosine Kinase. Biomedicines 2022; 10:biomedicines10051112. [PMID: 35625853 PMCID: PMC9138253 DOI: 10.3390/biomedicines10051112] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/09/2022] [Accepted: 05/09/2022] [Indexed: 12/17/2022] Open
Abstract
Src, a non-receptor tyrosine kinase, was first discovered as a prototype oncogene and has been shown to critical for cancer progression for a variety of tissues. Src activity is regulated by a number of post-translational modifications in response to various stimuli. Phosphorylations of Src Tyr419 (human; 416 in chicken) and Src Tyr530 (human; 527 in chicken) have been known to be critical for activation and inactivation of Src, respectively. Wnt signaling regulates a variety of cellular functions including for development and cell proliferation, and has a role in certain diseases such as cancer. Wnt signaling is carried out through two pathways: β-catenin-dependent canonical and β-catenin-independent non-canonical pathways as Wnt ligands bind to their receptors, Frizzled, LRP5/6, and ROR1/2. In addition, many signaling components including Axin, APC, Damm, Dishevelled, JNK kinase and Rho GTPases contribute to these canonical and non-canonical Wnt pathways. However, the communication between Wnt signaling and Src tyrosine kinase has not been well reviewed as Src regulates Wnt signaling through LRP6 tyrosine phosphorylation. GSK-3β phosphorylated by Wnt also regulates Src activity. As Wnt signaling and Src mutually regulate each other, it is noted that aberrant regulation of these components give rise to various diseases including typically cancer, and as such, merit a closer look.
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Affiliation(s)
- Jung Ki Min
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Hwee-Seon Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (H.-S.P.); (J.-I.K.)
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Yoon-Beom Lee
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Jae-Gyu Kim
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea; (H.-S.P.); (J.-I.K.)
- Genomic Medicine Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jae-Bong Park
- Department of Biochemistry, Hallym University College of Medicine, Chuncheon 25242, Korea; (J.K.M.); (Y.-B.L.); (J.-G.K.)
- Institute of Cell Differentiation and Aging, Hallym University College of Medicine, Chuncheon 24252, Korea
- Correspondence: ; Tel.: +82-33-248-2542; Fax: +82-33-244-8425
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17
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Fabro F, Lamfers MLM, Leenstra S. Advancements, Challenges, and Future Directions in Tackling Glioblastoma Resistance to Small Kinase Inhibitors. Cancers (Basel) 2022; 14:600. [PMID: 35158868 PMCID: PMC8833415 DOI: 10.3390/cancers14030600] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022] Open
Abstract
Despite clinical intervention, glioblastoma (GBM) remains the deadliest brain tumor in adults. Its incurability is partly related to the establishment of drug resistance, both to standard and novel treatments. In fact, even though small kinase inhibitors have changed the standard clinical practice for several solid cancers, in GBM, they did not fulfill this promise. Drug resistance is thought to arise from the heterogeneity of GBM, which leads the development of several different mechanisms. A better understanding of the evolution and characteristics of drug resistance is of utmost importance to improve the current clinical practice. Therefore, the development of clinically relevant preclinical in vitro models which allow careful dissection of these processes is crucial to gain insights that can be translated to improved therapeutic approaches. In this review, we first discuss the heterogeneity of GBM, which is reflected in the development of several resistance mechanisms. In particular, we address the potential role of drug resistance mechanisms in the failure of small kinase inhibitors in clinical trials. Finally, we discuss strategies to overcome therapy resistance, particularly focusing on the importance of developing in vitro models, and the possible approaches that could be applied to the clinic to manage drug resistance.
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Affiliation(s)
| | | | - Sieger Leenstra
- Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; (F.F.); (M.L.M.L.)
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18
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Ulfo L, Costantini PE, Di Giosia M, Danielli A, Calvaresi M. EGFR-Targeted Photodynamic Therapy. Pharmaceutics 2022; 14:241. [PMID: 35213974 PMCID: PMC8879084 DOI: 10.3390/pharmaceutics14020241] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/04/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) plays a pivotal role in the proliferation and metastatization of cancer cells. Aberrancies in the expression and activation of EGFR are hallmarks of many human malignancies. As such, EGFR-targeted therapies hold significant potential for the cure of cancers. In recent years, photodynamic therapy (PDT) has gained increased interest as a non-invasive cancer treatment. In PDT, a photosensitizer is excited by light to produce reactive oxygen species, resulting in local cytotoxicity. One of the critical aspects of PDT is to selectively transport enough photosensitizers to the tumors environment. Accordingly, an increasing number of strategies have been devised to foster EGFR-targeted PDT. Herein, we review the recent nanobiotechnological advancements that combine the promise of PDT with EGFR-targeted molecular cancer therapy. We recapitulate the chemistry of the sensitizers and their modes of action in PDT, and summarize the advantages and pitfalls of different targeting moieties, highlighting future perspectives for EGFR-targeted photodynamic treatment of cancer.
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Affiliation(s)
- Luca Ulfo
- Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum—Università di Bologna, Via Francesco Selmi 3, 40126 Bologna, Italy; (L.U.); (P.E.C.)
| | - Paolo Emidio Costantini
- Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum—Università di Bologna, Via Francesco Selmi 3, 40126 Bologna, Italy; (L.U.); (P.E.C.)
| | - Matteo Di Giosia
- Dipartimento di Chimica “Giacomo Ciamician”, Alma Mater Studiorum—Università di Bologna, Via Francesco Selmi 2, 40126 Bologna, Italy;
| | - Alberto Danielli
- Dipartimento di Farmacia e Biotecnologie, Alma Mater Studiorum—Università di Bologna, Via Francesco Selmi 3, 40126 Bologna, Italy; (L.U.); (P.E.C.)
| | - Matteo Calvaresi
- Dipartimento di Chimica “Giacomo Ciamician”, Alma Mater Studiorum—Università di Bologna, Via Francesco Selmi 2, 40126 Bologna, Italy;
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19
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Srisakuldee W, Nickel BE, Fandrich RR, Zhang F, Pasumarthi KBS, Kardami E. A Cardiac Mitochondrial FGFR1 Mediates the Antithetical Effects of FGF2 Isoforms on Permeability Transition. Cells 2021; 10:2735. [PMID: 34685716 PMCID: PMC8534529 DOI: 10.3390/cells10102735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 09/30/2021] [Accepted: 10/06/2021] [Indexed: 11/16/2022] Open
Abstract
Mitochondria, abundant organelles in high energy demand cells such as cardiomyocytes, can determine cell death or survival by regulating the opening of mitochondrial permeability transition pore, mPTP. We addressed the hypothesis that the growth factor FGF2, known to reside in intracellular locations, can directly influence mitochondrial susceptibility to mPTP opening. Rat cardiac subsarcolemmal (SSM) or interfibrillar (IFM) mitochondrial suspensions exposed directly to rat 18 kDa low molecular weight (Lo-) FGF2 isoform displayed increased resistance to calcium overload-induced mPTP, measured spectrophotometrically as "swelling", or as cytochrome c release from mitochondria. Inhibition of mitochondrial protein kinase C epsilon abrogated direct Lo-FGF2 mito-protection. Exposure to the rat 23 kDa high molecular weight (Hi) FGF2 isoform promoted cytochrome c release from SSM and IFM under nonstressed conditions. The effect of Hi-FGF2 was prevented by mPTP inhibitors, pre-exposure to Lo-FGF2, and okadaic acid, a serine/threonine phosphatase inhibitor. Western blotting and immunoelectron microscopy pointed to the presence of immunoreactive FGFR1 in cardiac mitochondria in situ. The direct mito-protective effect of Lo-FGF2, as well as the deleterious effect of Hi-FGF2, were prevented by FGFR1 inhibitors and FGFR1 neutralizing antibodies. We propose that intracellular FGF2 isoforms can modulate mPTP opening by interacting with mito-FGFR1 and relaying isoform-specific intramitochondrial signal transduction.
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Affiliation(s)
- Wattamon Srisakuldee
- Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- St. Boniface Research Centre, Institute of Cardiovascular Sciences, Winnipeg, MB R2H 2A6, Canada; (B.E.N.); (R.R.F.)
| | - Barbara E. Nickel
- St. Boniface Research Centre, Institute of Cardiovascular Sciences, Winnipeg, MB R2H 2A6, Canada; (B.E.N.); (R.R.F.)
| | - Robert R. Fandrich
- St. Boniface Research Centre, Institute of Cardiovascular Sciences, Winnipeg, MB R2H 2A6, Canada; (B.E.N.); (R.R.F.)
- Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Feixong Zhang
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; (F.Z.); (K.B.S.P.)
| | - Kishore B. S. Pasumarthi
- Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada; (F.Z.); (K.B.S.P.)
| | - Elissavet Kardami
- Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- St. Boniface Research Centre, Institute of Cardiovascular Sciences, Winnipeg, MB R2H 2A6, Canada; (B.E.N.); (R.R.F.)
- Department of Human Anatomy and Cell Sciences, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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20
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Vogt S, Ramzan R, Grossman LI, Singh KK, Ferguson-Miller S, Yoshikawa S, Lee I, Hüttemann M. Mitochondrial respiration is controlled by Allostery, Subunit Composition and Phosphorylation Sites of Cytochrome c Oxidase: A trailblazer's tale - Bernhard Kadenbach. Mitochondrion 2021; 60:228-233. [PMID: 34481964 DOI: 10.1016/j.mito.2021.08.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 08/27/2021] [Indexed: 12/30/2022]
Abstract
In memoriam of Bernhard Kadenbach: Although the main focus of his research was the structure, function, and regulation of mitochondrial cytochrome c oxidase (CytOx), he earlier studied the mitochondrial phosphate carrier and found an essential role of cardiolipin. Later, he discovered tissue-specific and developmental-specific protein isoforms of CytOx. Defective activity of CytOx is found with increasing age in human muscle and neuronal cells resulting in mitochondrial diseases. Kadenbach proposed a theory on the cause of oxidative stress, aging, and associated diseases stating that allosteric feedback inhibition of CytOx at high mitochondrial ATP/ADP ratios is essential for healthy living while stress-induced reversible dephosphorylation of CytOx results in the formation of excessive reactive oxygen species that trigger degenerative diseases. This article summarizes the main discoveries of Kadenbach related to mammalian CytOx and discusses their implications for human disease.
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Affiliation(s)
- Sebastian Vogt
- Department of Heart Surgery, Campus Marburg, University Hospital of Giessen and Marburg, D-35043 Marburg, Germany; Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany.
| | - Rabia Ramzan
- Department of Heart Surgery, Campus Marburg, University Hospital of Giessen and Marburg, D-35043 Marburg, Germany; Cardiovascular Research Laboratory, Biochemical-Pharmacological Center, Philipps-University Marburg, Karl-von-Frisch-Strasse 1, D-35043 Marburg, Germany
| | - Lawrence I Grossman
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Keshav K Singh
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Shelagh Ferguson-Miller
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, United States
| | - Shinya Yoshikawa
- Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1 Koto, Kamigori-cho, Ako-gun, Hyogo 678-1297, Japan
| | - Icksoo Lee
- College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do 31116, South Korea
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
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21
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Niemi NM, Pagliarini DJ. The extensive and functionally uncharacterized mitochondrial phosphoproteome. J Biol Chem 2021; 297:100880. [PMID: 34144036 PMCID: PMC8267538 DOI: 10.1016/j.jbc.2021.100880] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/07/2021] [Accepted: 06/14/2021] [Indexed: 11/06/2022] Open
Abstract
More than half a century ago, reversible protein phosphorylation was linked to mitochondrial metabolism through the regulation of pyruvate dehydrogenase. Since this discovery, the number of identified mitochondrial protein phosphorylation sites has increased by orders of magnitude, driven largely by technological advances in mass spectrometry-based phosphoproteomics. However, the majority of these modifications remain uncharacterized, rendering their function and relevance unclear. Nonetheless, recent studies have shown that disruption of resident mitochondrial protein phosphatases causes substantial metabolic dysfunction across organisms, suggesting that proper management of mitochondrial phosphorylation is vital for organellar and organismal homeostasis. While these data suggest that phosphorylation within mitochondria is of critical importance, significant gaps remain in our knowledge of how these modifications influence organellar function. Here, we curate publicly available datasets to map the extent of protein phosphorylation within mammalian mitochondria and to highlight the known functions of mitochondrial-resident phosphatases. We further propose models by which phosphorylation may affect mitochondrial enzyme activities, protein import and processing, and overall organellar homeostasis.
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Affiliation(s)
- Natalie M Niemi
- Department of Biochemistry & Molecular Biophysics, Washington University in St Louis, St Louis, Missouri, USA
| | - David J Pagliarini
- Departments of Cell Biology and Physiology, Biochemistry & Molecular Biophysics, and Genetics, Washington University in St Louis, St Louis, Missouri, USA; Morgridge Institute for Research, Madison, Wisconsin, USA; Department of Biochemistry, University of Madison-Wisconsin, Madison, Wisconsin, USA.
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22
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SRC Signaling in Cancer and Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:57-71. [PMID: 33123993 DOI: 10.1007/978-3-030-47189-7_4] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pioneering experiments performed by Harold Varmus and Mike Bishop in 1976 led to one of the most influential discoveries in cancer research and identified the first cancer-causing oncogene called Src. Later experimental and clinical evidence suggested that Src kinase plays a significant role in promoting tumor growth and progression and its activity is associated with poor patient survival. Thus, several Src inhibitors were developed and approved by FDA for treatment of cancer patients. Tumor microenvironment (TME) is a highly complex and dynamic milieu where significant cross-talk occurs between cancer cells and TME components, which consist of tumor-associated macrophages, fibroblasts, and other immune and vascular cells. Growth factors and chemokines activate multiple signaling cascades in TME and induce multiple kinases and pathways, including Src, leading to tumor growth, invasion/metastasis, angiogenesis, drug resistance, and progression. Here, we will systemically evaluate recent findings regarding regulation of Src and significance of targeting Src in cancer therapy.
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23
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Moro L. The Mitochondrial Proteome of Tumor Cells: A SnapShot on Methodological Approaches and New Biomarkers. BIOLOGY 2020; 9:biology9120479. [PMID: 33353059 PMCID: PMC7766083 DOI: 10.3390/biology9120479] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/12/2020] [Accepted: 12/16/2020] [Indexed: 12/12/2022]
Abstract
Simple Summary Mitochondria are central hubs of cellular signaling, energy metabolism, and redox balance. The plasticity of these cellular organelles is an essential requisite for the cells to cope with different stimuli and stress conditions. Cancer cells are characterized by changes in energy metabolism, mitochondrial signaling, and dynamics. These changes are driven by alterations in the mitochondrial proteome. For this reason, in the last years a focus of basic and cancer research has been the implementation and optimization of technologies to investigate changes in the mitochondrial proteome during cancer initiation and progression. This review presents an overview of the most used technologies to investigate the mitochondrial proteome and recent evidence on changes in the expression levels and delocalization of certain proteins in and out the mitochondria for shaping the functional properties of tumor cells. Abstract Mitochondria are highly dynamic and regulated organelles implicated in a variety of important functions in the cell, including energy production, fatty acid metabolism, iron homeostasis, programmed cell death, and cell signaling. Changes in mitochondrial metabolism, signaling and dynamics are hallmarks of cancer. Understanding whether these modifications are associated with alterations of the mitochondrial proteome is particularly relevant from a translational point of view because it may contribute to better understanding the molecular bases of cancer development and progression and may provide new potential prognostic and diagnostic biomarkers as well as novel molecular targets for anti-cancer treatment. Making an inventory of the mitochondrial proteins has been particularly challenging given that there is no unique consensus targeting sequence that directs protein import into mitochondria, some proteins are present at very low levels, while other proteins are expressed only in some cell types, in a particular developmental stage or under specific stress conditions. This review aims at providing the state-of-the-art on methodologies used to characterize the mitochondrial proteome in tumors and highlighting the biological relevance of changes in expression and delocalization of proteins in and out the mitochondria in cancer biology.
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Affiliation(s)
- Loredana Moro
- Institute of Biomembranes, Bioenergetic and Molecular Biotechnologies, National Research Council, Via Amendola 122/O, 70125 Bari, Italy
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24
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Cheikhi A, Anguiano T, Lasak J, Qian B, Sahu A, Mimiya H, Cohen CC, Wipf P, Ambrosio F, Barchowsky A. Arsenic Stimulates Myoblast Mitochondrial Epidermal Growth Factor Receptor to Impair Myogenesis. Toxicol Sci 2020; 176:162-174. [PMID: 32159786 PMCID: PMC7357174 DOI: 10.1093/toxsci/kfaa031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Arsenic exposure impairs muscle metabolism, maintenance, progenitor cell differentiation, and regeneration following acute injury. Low to moderate arsenic exposures target muscle fiber and progenitor cell mitochondria to epigenetically decrease muscle quality and regeneration. However, the mechanisms for how low levels of arsenic signal for prolonged mitochondrial dysfunction are not known. In this study, arsenic attenuated murine C2C12 myoblasts differentiation and resulted in abnormal undifferentiated myoblast proliferation. Arsenic prolonged ligand-independent phosphorylation of mitochondrially localized epidermal growth factor receptor (EGFR), a major driver of proliferation. Treating cells with a selective EGFR kinase inhibitor, AG-1478, prevented arsenic inhibition of myoblast differentiation. AG-1478 decreased arsenic-induced colocalization of pY845EGFR with mitochondrial cytochrome C oxidase subunit II, as well as arsenic-enhanced mitochondrial membrane potential, reactive oxygen species generation, and cell cycling. All of the arsenic effects on mitochondrial signaling and cell fate were mitigated or reversed by addition of mitochondrially targeted agents that restored mitochondrial integrity and function. Thus, arsenic-driven pathogenesis in skeletal muscle requires sustained mitochondrial EGFR activation that promotes progenitor cell cycling and proliferation at the detriment of proper differentiation. Collectively, these findings suggest that the arsenic-activated mitochondrial EGFR pathway drives pathogenic signaling for impaired myoblast metabolism and function.
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Affiliation(s)
- Amin Cheikhi
- Division of Geriatric Medicine, Department of Medicine
- Department of Environmental and Occupational Health
- Department of Physical Medicine and Rehabilitation
| | | | - Jane Lasak
- Department of Physical Medicine and Rehabilitation
| | - Baoli Qian
- Department of Environmental and Occupational Health
| | - Amrita Sahu
- Department of Physical Medicine and Rehabilitation
| | | | | | | | - Fabrisia Ambrosio
- Department of Environmental and Occupational Health
- Department of Physical Medicine and Rehabilitation
- McGowan Institute for Regenerative Medicine
- Department of Bioengineering
| | - Aaron Barchowsky
- Department of Environmental and Occupational Health
- Department of Bioengineering
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
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25
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Belli S, Esposito D, Servetto A, Pesapane A, Formisano L, Bianco R. c-Src and EGFR Inhibition in Molecular Cancer Therapy: What Else Can We Improve? Cancers (Basel) 2020; 12:E1489. [PMID: 32517369 PMCID: PMC7352780 DOI: 10.3390/cancers12061489] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 06/02/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023] Open
Abstract
The proto-oncogene c-Src is a non-receptor tyrosine kinase playing a key role in many cellular pathways, including cell survival, migration and proliferation. c-Src de-regulation has been observed in several cancer types, making it an appealing target for drug discovery efforts. Recent evidence emphasizes its crucial role not only in promoting oncogenic traits, but also in the acquisition and maintenance of cancer resistance to various chemotherapeutic or molecular target drugs. c-Src modulates epidermal growth factor receptor (EGFR) activation and amplifies its downstream oncogenic signals. In this review, we report several studies supporting c-Src kinase role in the intricate mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs). We further highlighted pre- and clinical progresses of combined treatment strategies made in recent years. Several pre-clinical data have encouraged the use of c-Src inhibitors in combination with EGFR inhibitors. However, clinical trials provided controversial outcomes in some cancer types. Despite c-Src inhibitors showed good tolerability in cancer patients, no incontrovertible and consistent clinical responses were recorded, supporting the idea that a better selection of patients is needed to improve clinical outcome. Currently, the identification of biological markers predictive of therapy response and the accurate molecular screening of cancer patients aimed to gain most clinical benefits become decisive and mandatory.
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Affiliation(s)
| | | | | | | | - Luigi Formisano
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy; (S.B.); (D.E.); (A.S.); (A.P.)
| | - Roberto Bianco
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy; (S.B.); (D.E.); (A.S.); (A.P.)
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26
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Hunter CA, Koc H, Koc EC. c-Src kinase impairs the expression of mitochondrial OXPHOS complexes in liver cancer. Cell Signal 2020; 72:109651. [PMID: 32335258 DOI: 10.1016/j.cellsig.2020.109651] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/16/2020] [Accepted: 04/17/2020] [Indexed: 12/27/2022]
Abstract
Src family kinases (SFKs) play a crucial role in the regulation of multiple cellular pathways, including mitochondrial oxidative phosphorylation (OXPHOS). Aberrant activities of one of the most predominant SFKs, c-Src, was identified as a fundamental cause for dysfunctional cell signaling and implicated in cancer development and metastasis, especially in human hepatocellular carcinoma (HCC). Recent work in our laboratory revealed that c-Src is implicated in the regulation of mitochondrial energy metabolism in cancer. In this study, we investigated the effect of c-Src expression on mitochondrial energy metabolism by examining changes in the expression and activities of OXPHOS complexes in liver cancer biopsies and cell lines. An increased expression of c-Src was correlated with an impaired expression of nuclear- and mitochondrial-encoded subunits of OXPHOS complexes I and IV, respectively, in metastatic biopsies and cell lines. Additionally, we observed a similar association between high c-Src and reduced OXPHOS complex expression and activity in mouse embryonic fibroblast (MEF) cell lines. Interestingly, the inhibition of c-Src kinase activity with the SFK inhibitor PP2 and c-Src siRNA stimulated the expression of complex I and IV subunits and increased their enzymatic activities in both cancer and normal cells. Evidence provided in this study reveals that c-Src impairs the expression and function of mitochondrial OXPHOS complexes, resulting in a significant defect in mitochondrial energy metabolism, which can be a contributing factor to the development and progression of liver cancer. Furthermore, our findings strongly suggest that SFK inhibitors should be used in the treatment of HCC and other cancers with aberrant c-Src kinase activity to improve mitochondrial energy metabolism.
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Affiliation(s)
- Caroline A Hunter
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States
| | - Hasan Koc
- Department of Pharmacological Science and Research, School of Pharmacy, Marshall University, Huntington, WV 25755, United States.
| | - Emine C Koc
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, United States.
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27
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Profiling of subcellular EGFR interactome reveals hnRNP A3 modulates nuclear EGFR localization. Oncogenesis 2020; 9:40. [PMID: 32321917 PMCID: PMC7176650 DOI: 10.1038/s41389-020-0225-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 04/04/2020] [Accepted: 04/07/2020] [Indexed: 12/19/2022] Open
Abstract
The aberrant subcellular translocation and distribution of epidermal growth factor receptor (EGFR) represent a major yet currently underappreciated cancer development mechanism in non-small cell lung cancer (NSCLC). In this study, we investigated the subcellular interactome of EGFR by using a spectral counting-based approach combined with liquid chromatography–tandem mass spectrometry to understand the associated protein networks involved in the tumorigenesis of NSCLC. A total of 54, 77, and 63 EGFR-interacting proteins were identified specifically in the cytosolic, mitochondrial, and nuclear fractions from a NSCLC cell line, respectively. Pathway analyses of these proteins using the KEGG database shown that the EGFR-interacting proteins of the cytosol and nucleus are involved in the ribosome and spliceosome pathways, respectively, while those of the mitochondria are involved in metabolizing propanoate, fatty acid, valine, leucine, and isoleucine. A selected nuclear EGFR-interacting protein, hnRNP A3, was found to modulate the accumulation of nuclear EGFR. Downregulation of hnRNP A3 reduced the nuclear accumulation of EGFR, and this was accompanied by reduced tumor growth ability in vitro and in vivo. These results indicate that variations in the subcellular translocation and distribution of EGFR within NSCLC cells could affect tumor progression.
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28
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Dual-target kinase drug design: Current strategies and future directions in cancer therapy. Eur J Med Chem 2020; 188:112025. [DOI: 10.1016/j.ejmech.2019.112025] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 12/18/2019] [Accepted: 12/29/2019] [Indexed: 12/12/2022]
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29
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Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy. Cancers (Basel) 2020; 12:cancers12010181. [PMID: 31936895 PMCID: PMC7017237 DOI: 10.3390/cancers12010181] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 01/08/2020] [Accepted: 01/08/2020] [Indexed: 12/24/2022] Open
Abstract
Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and -resistant non-small cell lung cancer.
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30
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EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming. Nat Commun 2019; 10:5033. [PMID: 31695034 PMCID: PMC6834558 DOI: 10.1038/s41467-019-13034-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Accepted: 10/14/2019] [Indexed: 12/13/2022] Open
Abstract
The molecular mechanisms driving metastatic progression in triple-negative breast cancer (TNBC) patients are poorly understood. In this study, we demonstrate that epidermal growth factor-like 9 (EGFL9) is significantly upregulated in basal-like breast cancer cells and associated with metastatic progression in breast tumor samples. Functionally, EGFL9 is both necessary and sufficient to enhance cancer cell migration and invasion, as well as distant metastasis. Mechanistically, we demonstrate that EGFL9 binds cMET, activating cMET-mediated downstream signaling. EGFL9 and cMET co-localize at both the cell membrane and within the mitochondria. We further identify an interaction between EGFL9 and the cytochrome c oxidase (COX) assembly factor COA3. Consequently, EGFL9 regulates COX activity and modulates cell metabolism, promoting a Warburg-like metabolic phenotype. Finally, we show that combined pharmacological inhibition of cMET and glycolysis reverses EGFL9-driven stemness. Our results identify EGFL9 as a therapeutic target for combating metastatic progression in TNBC. Triple-negative breast cancer is an aggressive form of the disease. Here, the authors identify EGFL9 as a mediator of metastasis in TNBC through interactions with cMET.
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31
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EGFR-c-Src-Mediated HDAC3 Phosphorylation Exacerbates Invasion of Breast Cancer Cells. Cells 2019; 8:cells8080930. [PMID: 31430896 PMCID: PMC6721651 DOI: 10.3390/cells8080930] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 08/08/2019] [Accepted: 08/14/2019] [Indexed: 01/09/2023] Open
Abstract
Breast cancer is one of the leading causes of morbidity and mortality among women. Epidermal growth factor receptor (EGFR) and proto-oncogene tyrosine-protein kinase Src (c-Src) are critical components of the signaling pathways that are associated with breast cancer. However, the regulatory mechanism of histone deacetylase 3 (HDAC3) in these pathways remains unclear. Using the Net Phos 3.1 program for the analysis of kinase consensus motifs, we found two c-Src-mediated putative phosphorylation sites, tyrosine (Tyr, Y)-328 and Y331 on HDAC3, and generated a phospho-specific HDAC3 antibody against these sites. c-Src-mediated phosphorylation was observed in the cells expressing wild-type HDAC3 (HDAC3WT), but not in cells overexpressing phosphorylation-defective HDAC3 (HDAC3Y328/331A). Phosphorylated HDAC3 showed relatively higher deacetylase activity, and PP2, which is a c-Src inhibitor, blocked HDAC3 phosphorylation and reduced its enzymatic activity. EGF treatment resulted in HDAC3 phosphorylation in both MDA-MB-231 and EGFR-overexpressing MCF7 (MCF7-EGFR) cells, but not in MCF7 cells. Total internal reflection fluorescence analysis showed that HDAC3 was recruited to the plasma membrane following EGF stimulation. HDAC3 inhibition with either c-Src knockdown or PP2 treatment significantly ameliorated the invasiveness of breast cancer cells. Altogether, our findings reveal an EGF signaling cascade involving EGFR, c-Src, and HDAC3 in breast cancer cells.
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32
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Transcriptome analysis provides insights into the molecular mechanisms responsible for evisceration behavior in the sea cucumber Apostichopus japonicus. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY D-GENOMICS & PROTEOMICS 2019; 30:143-157. [PMID: 30851504 DOI: 10.1016/j.cbd.2019.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 02/25/2019] [Accepted: 02/26/2019] [Indexed: 01/05/2023]
Abstract
The sea cucumber Apostichopus japonicus (Selenka) is a valuable economic species in Southeast Asia. It has many fascinating behavioral characteristics, such as autolysis, aestivation, regeneration, and evisceration, thus it is a notable species for studies of special behaviors. Evisceration and autotomy are controlled by the neural network and involve a complicated physiological process. The occurrence of evisceration behavior in sea cucumbers is strongly related to their environment, and it negatively impacts their economic value. Evisceration behavior plays a pivotal role in the survival of A. japonicus, and when it is induced by dramatic changes in the coastal ecological environment and the aquaculture setting it can strongly affect the economic performance of this species. Although numerous studies have focused on intestinal regeneration of A. japonicus, less is known about evisceration behavior, especially its underlying molecular mechanisms. Thus, identification of genes that regulate evisceration in the sea cucumber likely will provide a scientific explanation for this significant specific behavior. In this study, Illumina sequencing (RNA-Seq) was performed on A. japonicus specimens in three states: normal (TCQ), eviscerating (TCZ), and 3 h after evisceration (TCH). In total, 129,905 unigenes were generated with an N50 length of 2651 base pairs, and 54,787 unigenes were annotated from seven functional databases (KEGG, KOG, GO, NR, NT, Interpro, and Swiss-Prot). Additionally, 190, 191, and 320 genes were identified as differentially expressed genes (DEGs) in the comparisons of TCQ vs. TCZ, TCZ vs. TCH, and TCQ vs. TCH, respectively. These DEGs mapped to 157, 113, and 190 signaling pathways in the KEGG database, respectively. KEGG analyses also revealed that potential DEGs enriched in the categories of "environmental information processing," "organismal system," "metabolism," and "cellular processes," and they were involved in evisceration behavior in A. japonicus. These DEGs are related to muscle contraction, hormone and neurotransmitter secretion, nerve and muscle damage, energy support, cellular stress, and apoptosis. In conclusion, through our comparative analysis of A. japonicus in different stages, we identified many candidate evisceration-related genes and signaling pathways that likely are involved in evisceration behavior. These results should help further elucidate the mechanisms underlying evisceration behavior in sea cucumbers.
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Kalpage HA, Bazylianska V, Recanati MA, Fite A, Liu J, Wan J, Mantena N, Malek MH, Podgorski I, Heath EI, Vaishnav A, Edwards BF, Grossman LI, Sanderson TH, Lee I, Hüttemann M. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis. FASEB J 2019; 33:1540-1553. [PMID: 30222078 PMCID: PMC6338631 DOI: 10.1096/fj.201801417r] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 08/14/2018] [Indexed: 02/02/2023]
Abstract
Cytochrome c (Cyt c) plays a vital role in the mitochondrial electron transport chain (ETC). In addition, it is a key regulator of apoptosis. Cyt c has multiple other functions including ROS production and scavenging, cardiolipin peroxidation, and mitochondrial protein import. Cyt c is tightly regulated by allosteric mechanisms, tissue-specific isoforms, and post-translational modifications (PTMs). Distinct residues of Cyt c are modified by PTMs, primarily phosphorylations, in a highly tissue-specific manner. These modifications downregulate mitochondrial ETC flux and adjust the mitochondrial membrane potential (ΔΨm), to minimize reactive oxygen species (ROS) production under normal conditions. In pathologic and acute stress conditions, such as ischemia-reperfusion, phosphorylations are lost, leading to maximum ETC flux, ΔΨm hyperpolarization, excessive ROS generation, and the release of Cyt c. It is also the dephosphorylated form of the protein that leads to maximum caspase activation. We discuss the complex regulation of Cyt c and propose that it is a central regulatory step of the mammalian ETC that can be rate limiting in normal conditions. This regulation is important because it maintains optimal intermediate ΔΨm, limiting ROS generation. We examine the role of Cyt c PTMs, including phosphorylation, acetylation, methylation, nitration, nitrosylation, and sulfoxidation and consider their potential biological significance by evaluating their stoichiometry.-Kalpage, H. A., Bazylianska, V., Recanati, M. A., Fite, A., Liu, J., Wan, J., Mantena, N., Malek, M. H., Podgorski, I., Heath, E. I., Vaishnav, A., Edwards, B. F., Grossman, L. I., Sanderson, T. H., Lee, I., Hüttemann, M. Tissue-specific regulation of cytochrome c by post-translational modifications: respiration, the mitochondrial membrane potential, ROS, and apoptosis.
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Affiliation(s)
- Hasini A. Kalpage
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Viktoriia Bazylianska
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Maurice A. Recanati
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
- Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Alemu Fite
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Jenney Liu
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Junmei Wan
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Nikhil Mantena
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Moh H. Malek
- Department of Health Care Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA
- Cardiovascular Research Institute, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Izabela Podgorski
- Department of Pharmacology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Elizabeth I. Heath
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Asmita Vaishnav
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Brian F. Edwards
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Lawrence I. Grossman
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Thomas H. Sanderson
- Cardiovascular Research Institute, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
- Department of Emergency Medicine, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, USA
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, University of Michigan, Ann Arbor, Michigan, USA
| | - Icksoo Lee
- College of Medicine, Dankook University, Cheonan-si, Chungcheongnam-do, South Korea
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
- Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
- Cardiovascular Research Institute, Wayne State University School of Medicine, Wayne State University, Detroit, Michigan, USA
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Wang YN, Lee HH, Hung MC. A novel ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases. J Biomed Sci 2018; 25:83. [PMID: 30449278 PMCID: PMC6241042 DOI: 10.1186/s12929-018-0484-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 11/01/2018] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ribonuclease is known to participate in host defense system against pathogens, such as parasites, bacteria, and virus, which results in innate immune response. Nevertheless, its potential impact to host cells remains unclear. Of interest, several ribonucleases do not act as catalytically competent enzymes, suggesting that ribonucleases may be associated with certain intrinsic functions other than their ribonucleolytic activities. Most recently, human pancreatic ribonuclease 5 (hRNase5; also named angiogenin; hereinafter referred to as hRNase5/ANG), which belongs to the human ribonuclease A superfamily, has been demonstrated to function as a ligand of epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase family. As a newly identified EGFR ligand, hRNase5/ANG associates with EGFR and stimulates EGFR and the downstream signaling in a catalytic-independent manner. Notably, hRNase5/ANG, whose level in sera of pancreatic cancer patients, serves as a non-invasive serum biomarker to stratify patients for predicting the sensitivity to EGFR-targeted therapy. Here, we describe the hRNase5/ANG-EGFR pair as an example to highlight a ligand-receptor relationship between families of ribonucleases and receptor tyrosine kinases, which are thought as two unrelated protein families associated with distinct biological functions. The notion of serum biomarker-guided EGFR-targeted therapies will also be discussed. Furthering our understanding of this novel ligand-receptor interaction will shed new light on the search of ligands for their cognate receptors, especially those orphan receptors without known ligands, and deepen our knowledge of the fundamental research in membrane receptor biology and the translational application toward the development of precision medicine.
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Affiliation(s)
- Ying-Nai Wang
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030 USA
| | - Heng-Huan Lee
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030 USA
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030 USA
- Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030 USA
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, 404 Taiwan
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Naderi-Meshkin H, Ahmadiankia N. Cancer metastasis versus stem cell homing: Role of platelets. J Cell Physiol 2018; 233:9167-9178. [PMID: 30105746 DOI: 10.1002/jcp.26937] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Accepted: 06/12/2018] [Indexed: 12/12/2022]
Abstract
One of the major obstacles in achieving a successful stem cell therapy is insufficient homing of transplanted cells. To overcome this obstacle, understanding the underlying mechanisms of stem cell homing is of obvious importance. Central to this review is the concept that cancer metastasis can be viewed as a role model to build up a comprehensive concept of stem cell homing. In this novel perspective, the prosurvival choices of the cancerous cells in the bloodstream, their arrest, extravasation, and proliferation at the secondary site can be exploited in favor of targeted stem cell homing. To date, tumor cells have been found to employ a wide variety of strategies to promote metastasis. One of these strategies is through their ability to activate platelets and subsequently activated platelets serve cancer cell survival and metastasis. Accordingly, in the first part of this review the roles of platelets in cancer metastasis as well as stem cell homing are discussed. Next, we provide some lessons learned from cancer metastasis in favor of developing strategies for improvement of stem cell homing with emphasis on the role of platelets. Based on direct or indirect evidence from metastasis, strategies such as manipulation of stem cells to enhance interaction with platelets, preconditioning-pretreatment of stem cells with platelets in vitro, and coinjection of both stem cells and platelets are proposed to improve stem cell homing.
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Affiliation(s)
- Hojjat Naderi-Meshkin
- Stem Cells and Regenerative Medicine Research Group, Iranian Academic Center for Education, Culture Research (ACECR), Khorasan Razavi Branch, Mashhad, Iran
| | - Naghmeh Ahmadiankia
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.,Cancer Prevention Research Center, Shahroud University of Medical Sciences, Shahroud, Iran
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36
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Yang L, He Z, Yao J, Tan R, Zhu Y, Li Z, Guo Q, Wei L. Regulation of AMPK-related glycolipid metabolism imbalances redox homeostasis and inhibits anchorage independent growth in human breast cancer cells. Redox Biol 2018; 17:180-191. [PMID: 29702405 PMCID: PMC6006728 DOI: 10.1016/j.redox.2018.04.016] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/16/2018] [Accepted: 04/17/2018] [Indexed: 12/25/2022] Open
Abstract
Breast cancer is one of the most lethal tumors in the world, among which 15% are triple-negative breast cancers (TNBCs) with higher metastasis and lower survival rate. Anoikis resistance is a key process during tumor metastasis, which is usually accompanied with metabolism reprogram. In this study, we established an anchorage independent growth model for MDA-MB-231 cells and investigated the changes in metabolism and redox homeostasis. Results showed that during detached-growth, MDA-MB-231 cells tend to generate ATP through fatty acid oxidation (FAO), instead of glycolysis. Amount of glucose was used for pentose phosphate pathway (PPP) to keep redox balance. Moreover, we discovered that a synthesized flavonoid derivative GL-V9, exhibited a potent inhibitory effect on the anchorage independent growth of TNBCs in vitro and anti-metastasis effect in vivo. In terms of the mechanism, GL-V9 could promote the expression and activity of AMPK, leading to the decrease of G6PD and the increase of p-ACC. Thus, the level of PPP was suppressed, whereas FAO was highly enhanced. The reprogram of glycolipid metabolism destroyed the redox balance ultimately and induced cell death. This paper indicated a novel regulating mechanism of redox homeostasis involving with glycolipid metabolism, and provided a potential candidate for the anti-metastatic therapy of TNBCs.
Instead of glycolysis, FAO is the dominant way for ATP generation in anchorage independent growth. Glucose in cells detached from EMC is used for PPP to resist the ROS form OXPHOS. GL-V9 inhibits anchorage independent growth via imbalancing the redox homeostasis. AMPK is the critical regulator in GL-V9-induced glycolipid metabolism reprogram.
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Affiliation(s)
- Lin Yang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Zihao He
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Jingyue Yao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Renxiang Tan
- State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, 138 Xinlin Road, Nanjing 210023, People's Republic of China
| | - Yejin Zhu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Zhiyu Li
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China
| | - Qinglong Guo
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
| | - Libin Wei
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
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37
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Velpula KK, Guda MR, Sahu K, Tuszynski J, Asuthkar S, Bach SE, Lathia JD, Tsung AJ. Metabolic targeting of EGFRvIII/PDK1 axis in temozolomide resistant glioblastoma. Oncotarget 2018; 8:35639-35655. [PMID: 28410193 PMCID: PMC5482605 DOI: 10.18632/oncotarget.16767] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 02/28/2017] [Indexed: 01/15/2023] Open
Abstract
Glioblastomas are characterized by amplification of EGFR. Approximately half of tumors with EGFR over-expression also express a constitutively active ligand independent EGFR variant III (EGFRvIII). While current treatments emphasize surgery followed by radiation and chemotherapy with Temozolomide (TMZ), acquired chemoresistance is a universal feature of recurrent GBMs. To mimic the GBM resistant state, we generated an in vitro TMZ resistant model and demonstrated that dichloroacetate (DCA), a metabolic inhibitor of pyruvate dehydrogenase kinase 1 (PDK1), reverses the Warburg effect. Microarray analysis conducted on the TMZ resistant cells with their subsequent treatment with DCA revealed PDK1 as its sole target. DCA treatment also induced mitochondrial membrane potential change and apoptosis as evidenced by JC-1 staining and electron microscopic studies. Computational homology modeling and docking studies confirmed DCA binding to EGFR, EGFRvIII and PDK1 with high affinity. In addition, expression of EGFRvIII was comparable to PDK1 when compared to EGFR in GBM surgical specimens supporting our in silico prediction data. Collectively our current study provides the first in vitro proof of concept that DCA reverses the Warburg effect in the setting of EGFRvIII positivity and TMZ resistance leading to GBM cytotoxicity, implicating cellular tyrosine kinase signaling in cancer cell metabolism.
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Affiliation(s)
- Kiran K Velpula
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.,Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Maheedhara R Guda
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Kamlesh Sahu
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | - Jack Tuszynski
- Department of Oncology, University of Alberta, Edmonton, AB, Canada
| | - Swapna Asuthkar
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Sarah E Bach
- Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Justin D Lathia
- Department of Cellular and Molecular medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Andrew J Tsung
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.,Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.,Illinois Neurological Institute, Peoria, IL, USA
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38
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An Z, Aksoy O, Zheng T, Fan QW, Weiss WA. Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 2018; 37:1561-1575. [PMID: 29321659 PMCID: PMC5860944 DOI: 10.1038/s41388-017-0045-7] [Citation(s) in RCA: 429] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 10/04/2017] [Accepted: 10/05/2017] [Indexed: 01/05/2023]
Abstract
Amplification of epidermal growth factor receptor (EGFR) and its active mutant EGFRvIII occurs frequently in glioblastoma (GBM). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors (TKIs) or antibodies has only shown limited efficacy in patients. Here we discuss signaling pathways mediated by EGFR/EGFRvIII, current therapeutics, and novel strategies to target EGFR/EGFRvIII-amplified GBM.
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Affiliation(s)
- Zhenyi An
- Department of Neurology, University of California, San Francisco, CA, USA
| | - Ozlem Aksoy
- Department of Neurology, University of California, San Francisco, CA, USA
| | - Tina Zheng
- Department of Neurology, University of California, San Francisco, CA, USA
| | - Qi-Wen Fan
- Department of Neurology, University of California, San Francisco, CA, USA
| | - William A Weiss
- Department of Neurology, University of California, San Francisco, CA, USA.
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
- Department of Neurological Surgery, University of California, San Francisco, CA, USA.
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39
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Tomer D, Chippalkatti R, Mitra K, Rikhy R. ERK regulates mitochondrial membrane potential in fission deficient Drosophila follicle cells during differentiation. Dev Biol 2018; 434:48-62. [DOI: 10.1016/j.ydbio.2017.11.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Revised: 11/04/2017] [Accepted: 11/15/2017] [Indexed: 01/10/2023]
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40
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Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol 2018; 12:3-20. [PMID: 29124875 PMCID: PMC5748484 DOI: 10.1002/1878-0261.12155] [Citation(s) in RCA: 992] [Impact Index Per Article: 141.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 10/23/2017] [Accepted: 10/26/2017] [Indexed: 12/31/2022] Open
Abstract
The physiological function of the epidermal growth factor receptor (EGFR) is to regulate epithelial tissue development and homeostasis. In pathological settings, mostly in lung and breast cancer and in glioblastoma, the EGFR is a driver of tumorigenesis. Inappropriate activation of the EGFR in cancer mainly results from amplification and point mutations at the genomic locus, but transcriptional upregulation or ligand overproduction due to autocrine/paracrine mechanisms has also been described. Moreover, the EGFR is increasingly recognized as a biomarker of resistance in tumors, as its amplification or secondary mutations have been found to arise under drug pressure. This evidence, in addition to the prominent function that this receptor plays in normal epithelia, has prompted intense investigations into the role of the EGFR both at physiological and at pathological level. Despite the large body of knowledge obtained over the last two decades, previously unrecognized (herein defined as 'noncanonical') functions of the EGFR are currently emerging. Here, we will initially review the canonical ligand-induced EGFR signaling pathway, with particular emphasis to its regulation by endocytosis and subversion in human tumors. We will then focus on the most recent advances in uncovering noncanonical EGFR functions in stress-induced trafficking, autophagy, and energy metabolism, with a perspective on future therapeutic applications.
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Affiliation(s)
- Sara Sigismund
- Fondazione Istituto FIRC di Oncologia Molecolare (IFOM)MilanItaly
| | - Daniele Avanzato
- Department of OncologyUniversity of Torino Medical SchoolItaly,Candiolo Cancer InstituteFPO ‐ IRCCSCandiolo, TorinoItaly
| | - Letizia Lanzetti
- Department of OncologyUniversity of Torino Medical SchoolItaly,Candiolo Cancer InstituteFPO ‐ IRCCSCandiolo, TorinoItaly
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41
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Maisel S, Broka D, Schroeder J. Intravesicular epidermal growth factor receptor subject to retrograde trafficking drives epidermal growth factor-dependent migration. Oncotarget 2017; 9:6463-6477. [PMID: 29464085 PMCID: PMC5814225 DOI: 10.18632/oncotarget.23766] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 12/23/2017] [Indexed: 12/31/2022] Open
Abstract
The Epidermal Growth Factor Receptor (EGFR) is frequently mutated and overexpressed in metastatic cancer. Although EGFR is a transmembrane tyrosine kinase localized to the basolateral membrane in normal epithelium, it is frequently found intracellularly localized in transformed cells. We have previously demonstrated the epithelial adaptor protein mucin 1 (MUC1) alters trafficking of EGFR, inhibiting its degradation and promoting its translocation to the nucleus, where it can directly modulate gene transcription. Here, we demonstrate that MUC1 promotes the retention of EGF-bound EGFR in Early Endosome Antigen1 (EEA1)-positive vesicles while preventing its trafficking to the lysosome. These events result in the accumulation of endosomal vesicles harboring active receptor throughout the cell and a reorganization of the actin cytoskeleton. EGF-dependent cell migration and filopodia formation is reliant upon this altered trafficking, and can be prevented by blocking retrograde trafficking. Together, these results indicate that intracellular EGFR may play an essential role in cancer metastasis and a potential mechanism for the failure of therapeutic antibodies in EGFR-driven metastatic breast cancer.
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Affiliation(s)
- Sabrina Maisel
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA.,Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Derrick Broka
- Arizona Cancer Center, University of Arizona, Tucson, AZ, USA
| | - Joyce Schroeder
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA.,Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.,Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ, USA.,BIO5 Institute, University of Arizona, Tucson, AZ, USA
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Dual "mAb" HER family blockade in head and neck cancer human cell lines combined with photon therapy. Sci Rep 2017; 7:12207. [PMID: 28939847 PMCID: PMC5610257 DOI: 10.1038/s41598-017-12367-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 09/07/2017] [Indexed: 01/02/2023] Open
Abstract
Head and neck cancer stem cells (CSCs) are highly resistant to treatment. When EGFR is overexpressed in head and neck squamous cell carcinoma (HNSCC), HER2 and HER3 are also expressed. The aim of the present study was to investigate the effect of HER1/2/3 blockade through a combination of cetuximab and pertuzumab, with or without photon irradiation, on the proliferation and migration/invasion capabilities of an HNSCC chemo- and radioresistant human cell line (SQ20B) and its corresponding stem cell subpopulation. Cell proliferation, migration and invasion were studied after treatment with cetuximab +/− pertuzumab +/− 10 Gy photon irradiation. EGFR, phospho-EGFR, HER2 and HER3 protein expression levels were studied. Activation or inhibition of the RAS/MAPK and AKT-mTOR downstream signalling cascades was investigated through phospho-AKT and phospho-MEK1/2 expression. Cetuximab strongly inhibited SQ20B and FaDu cell proliferation, migration and invasion, whereas it had little effect on SQ20B-CSCs. Cetuximab–pertuzumab combined with radiation significantly inhibited SQ20B and FaDu cell and SQ20B-CSC proliferation, migration and invasion. Cetuximab–pertuzumab with 10 Gy photon irradiation switched off both phospho-AKT and phospho-MEK1/2 expression in the three populations. The triple therapy is therefore thought to inhibit SQ20B cells, SQ20B-CSCs and FaDu cells through an AKT-mTOR and Ras-MAPK downstream signalling blockade.
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Lim L, Mastragostino R, Ng K, Zheng G, Wilson BC. Can photoacoustic imaging quantify surface-localized J-aggregating nanoparticles? JOURNAL OF BIOMEDICAL OPTICS 2017; 22:76008. [PMID: 28703256 DOI: 10.1117/1.jbo.22.7.076008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 06/21/2017] [Indexed: 05/07/2023]
Abstract
We investigate the feasibility of photoacoustic (PA) imaging to quantify the concentration of surface-localized nanoparticles, using tissue-mimicking phantoms and imaging with a commercial PA instrument at 815 nm and a linear-array transducer at a center frequency of 40 MHz. The nanoparticles were J-aggregating porphysomes (JNP) comprising self-assembling, all-organic porphyrin-lipid micelles with a molar absorption coefficient of 8.7×108 cm−1 M−1 at this wavelength. The PA signal intensity versus JNP areal concentration followed a sigmoidal curve with a reproducible linear range of ∼17 fmol/mm2 to 11 pmol/mm2, i.e., ∼3 orders of magnitude with ±34% error. For physiologically-relevant conditions (i.e., optical scattering-dominated tissues: transport albedo >0.8) and JNP concentrations above ∼330 fmol/mm2, the PA signal depends only on the nanoparticle concentration. Otherwise, independent measurement of the optical absorption and scattering properties of the underlying tissue is required for accurate quantification. The implications for surface PA imaging, such as in the use of targeted nanoparticles applied topically to tissue as in endoscopic diagnosis, are considered.
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Affiliation(s)
- Liang Lim
- University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Robert Mastragostino
- University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Kenneth Ng
- University of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
| | - Gang Zheng
- University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, CanadabUniversity of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
| | - Brian C Wilson
- University Health Network, Princess Margaret Cancer Centre, Toronto, Ontario, CanadabUniversity of Toronto, Department of Medical Biophysics, Toronto, Ontario, Canada
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de Sousa Mesquita AP, de Araújo Lopes S, Pernambuco Filho PCA, Nader HB, Lopes CC. Acquisition of anoikis resistance promotes alterations in the Ras/ERK and PI3K/Akt signaling pathways and matrix remodeling in endothelial cells. Apoptosis 2017; 22:1116-1137. [DOI: 10.1007/s10495-017-1392-0] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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45
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Li H, You L, Xie J, Pan H, Han W. The roles of subcellularly located EGFR in autophagy. Cell Signal 2017; 35:223-230. [PMID: 28428083 DOI: 10.1016/j.cellsig.2017.04.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 04/14/2017] [Accepted: 04/15/2017] [Indexed: 12/11/2022]
Abstract
The epidermal growth factor receptor (EGFR) is a well-studied receptor-tyrosine kinase that serves vital roles in regulation of organ development and cancer progression. EGFR not only exists on the plasma membrane, but also widely expressed in the nucleus, endosomes, and mitochondria. Most recently, several lines of evidences indicated that autophagy is regulated by EGFR in kinase-active and -independent manners. In this review, we summarized recent advances in our understanding of the functions of different subcellularly located EGFR on autophagy. Specifically, plasma membrane- and cytoplasm-located EGFR (pcEGFR) acts as a tyrosine kinase to regulate autophagy via the PI3K/AKT1/mTOR, RAS/MAPK1/3, and STAT3 signaling pathways. The kinase-independent function of pcEGFR inhibits autophagy by maintaining SLC5A1-regulated intracellular glucose level. Endosome-located EGFR phosphorylates and inhibits Beclin1 to suppress autophagy, while kinase-independent endosome-located EGFR releases Beclin1 from the Rubicon-Beclin1 complex to increase autophagy. Additionally, the nuclear EGFR activates PRKDC/PNPase/MYC signaling to inhibit autophagy. Although the role of mitochondria-located EGFR in autophagy is largely unexplored, the production of ATP and reactive oxygen species mediated by mitochondrial dynamics is most likely to influence autophagy.
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Affiliation(s)
- Hongsen Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangkun You
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jiansheng Xie
- Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Weidong Han
- Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
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46
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Bauman JE, Duvvuri U, Gooding WE, Rath TJ, Gross ND, Song J, Jimeno A, Yarbrough WG, Johnson FM, Wang L, Chiosea S, Sen M, Kass J, Johnson JT, Ferris RL, Kim S, Hirsch FR, Ellison K, Flaherty JT, Mills GB, Grandis JR. Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer. JCI Insight 2017; 2:e90449. [PMID: 28352657 DOI: 10.1172/jci.insight.90449] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.
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Affiliation(s)
| | - Umamaheswar Duvvuri
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - William E Gooding
- Biostatistics Facility, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
| | - Tanya J Rath
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Neil D Gross
- Department of Otolaryngology - Head and Neck Surgery, Oregon Health Sciences University, Portland, Oregon, USA
| | | | - Antonio Jimeno
- Division of Medical Oncology University of Colorado, Denver, Colorado, USA
| | - Wendell G Yarbrough
- Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee, USA
| | - Faye M Johnson
- Department of Thoracic/Head and Neck Medical Oncology, MD Anderson Cancer Center, Houston, Texas, USA
| | - Lin Wang
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Simion Chiosea
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Malabika Sen
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jason Kass
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jonas T Johnson
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Robert L Ferris
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Seungwon Kim
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Fred R Hirsch
- Department of Medicine, University of Colorado, Denver, Colorado, USA
| | - Kimberly Ellison
- Department of Medicine, University of Colorado, Denver, Colorado, USA
| | | | - Gordon B Mills
- Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas, USA
| | - Jennifer R Grandis
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Stram AR, Payne RM. Post-translational modifications in mitochondria: protein signaling in the powerhouse. Cell Mol Life Sci 2016; 73:4063-73. [PMID: 27233499 PMCID: PMC5045789 DOI: 10.1007/s00018-016-2280-4] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Revised: 05/16/2016] [Accepted: 05/19/2016] [Indexed: 02/03/2023]
Abstract
There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer, and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post-translational processing and signaling mechanisms in mitochondria, and their implications in health and disease.
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Affiliation(s)
- Amanda R Stram
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut St., Room R4-302b, Indianapolis, IN, 46202, USA
| | - R Mark Payne
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.
- Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, 1044 W. Walnut St., Room R4-302b, Indianapolis, IN, 46202, USA.
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Bhushan B, Chavan H, Borude P, Xie Y, Du K, McGill MR, Lebofsky M, Jaeschke H, Krishnamurthy P, Apte U. Dual Role of Epidermal Growth Factor Receptor in Liver Injury and Regeneration after Acetaminophen Overdose in Mice. Toxicol Sci 2016; 155:363-378. [PMID: 28123000 DOI: 10.1093/toxsci/kfw213] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) plays a crucial role in hepatocyte proliferation. Its role in acetaminophen (APAP)-mediated hepatotoxicity and subsequent liver regeneration is completely unknown. Role of EGFR after APAP-overdose in mice was studied using pharmacological inhibition strategy. Rapid, sustained and dose-dependent activation of EGFR was noted after APAP-treatment in mice, which was triggered by glutathione depletion. EGFR-activation was also observed in primary human hepatocytes after APAP-treatment, preceding elevation of toxicity markers. Treatment of mice with an EGFR-inhibitor (EGFRi), Canertinib, 1h post-APAP resulted in robust inhibition of EGFR-activation and a striking reduction in APAP-induced liver injury. Metabolic activation of APAP, formation of APAP-protein adducts, APAP-mediated JNK-activation and its mitochondrial translocation were not altered by EGFRi. Interestingly, EGFR rapidly translocated to mitochondria after APAP-treatment. EGFRi-treatment abolished mitochondrial EGFR activity, prevented APAP-mediated mitochondrial dysfunction/oxidative-stress and release of endonucleases from mitochondria, which are responsible for DNA-damage/necrosis. Treatment with N-acetylcysteine (NAC), 4h post-APAP in mice did not show any protection but treatment of EGFRi in combination with NAC showed decrease in liver injury. Finally, delayed treatment with EGFRi, 12-h post-APAP, did not alter peak injury but caused impairment of liver regeneration resulting in sustained injury and decreased survival after APAP overdose in mice. Impairment of regeneration was due to inhibition of cyclinD1 induction and cell cycle arrest. Our study has revealed a new dual role of EGFR both in initiation of APAP-injury and in stimulation of subsequent compensatory regeneration after APAP-overdose.
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Affiliation(s)
- Bharat Bhushan
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Hemantkumar Chavan
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Prachi Borude
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Yuchao Xie
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Kuo Du
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Mitchell R McGill
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Margitta Lebofsky
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Partha Krishnamurthy
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
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49
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Cheng ML, Chi LM, Wu PR, Ho HY. Dehydroepiandrosterone-induced changes in mitochondrial proteins contribute to phenotypic alterations in hepatoma cells. Biochem Pharmacol 2016; 117:20-34. [DOI: 10.1016/j.bcp.2016.08.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2016] [Accepted: 08/04/2016] [Indexed: 10/21/2022]
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50
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Che TF, Lin CW, Wu YY, Chen YJ, Han CL, Chang YL, Wu CT, Hsiao TH, Hong TM, Yang PC. Mitochondrial translocation of EGFR regulates mitochondria dynamics and promotes metastasis in NSCLC. Oncotarget 2016; 6:37349-66. [PMID: 26497368 PMCID: PMC4741934 DOI: 10.18632/oncotarget.5736] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Accepted: 10/06/2015] [Indexed: 01/01/2023] Open
Abstract
Dysfunction of the mitochondria is well-known for being associated with cancer progression. In the present study, we analyzed the mitochondria proteomics of lung cancer cell lines with different invasion abilities and found that EGFR is highly expressed in the mitochondria of highly invasive non-small-cell lung cancer (NSCLC) cells. EGF induces the mitochondrial translocation of EGFR; further, it leads to mitochondrial fission and redistribution in the lamellipodia, upregulates cellular ATP production, and enhances motility in vitro and in vivo. Moreover, EGFR can regulate mitochondrial dynamics by interacting with Mfn1 and disturbing Mfn1 polymerization. Overexpression of Mfn1 reverses the phenotypes resulting from EGFR mitochondrial translocation. We show that the mitochondrial EGFR expressions are higher in paired samples of the metastatic lymph node as compared with primary lung tumor and are inversely correlated with the overall survival in NSCLC patients. Therefore, our results demonstrate that besides the canonical role of EGFR as a receptor tyrosine, the mitochondrial translocation of EGFR may enhance cancer invasion and metastasis through regulating mitochondria dynamics.
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Affiliation(s)
- Ting-Fang Che
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Ching-Wen Lin
- Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan
| | - Yi-Ying Wu
- Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan
| | - Yu-Ju Chen
- Institute of Chemistry, Academia Sinica 115, Taipei, Taiwan
| | - Chia-Li Han
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University 110, Taipei, Taiwan
| | - Yih-leong Chang
- Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Chen-Tu Wu
- Department of Pathology and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Tzu-Hung Hsiao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
| | - Tse-Ming Hong
- Institute of Clinical Medicine, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan
| | - Pan-Chyr Yang
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.,Institute of Biomedical Science, Academia Sinica, Taipei 115, Taiwan.,NTU Center for Genomic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.,Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
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