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Rajendran D, Oon CE. Navigating therapeutic prospects by modulating autophagy in colorectal cancer. Life Sci 2024; 358:123121. [PMID: 39389340 DOI: 10.1016/j.lfs.2024.123121] [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: 06/13/2024] [Revised: 09/25/2024] [Accepted: 10/05/2024] [Indexed: 10/12/2024]
Abstract
Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.
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Affiliation(s)
- Deepa Rajendran
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
| | - Chern Ein Oon
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
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2
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Scarini JF, Gonçalves MWA, de Lima-Souza RA, Lavareze L, de Carvalho Kimura T, Yang CC, Altemani A, Mariano FV, Soares HP, Fillmore GC, Egal ESA. Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets. Front Oncol 2024; 14:1275330. [PMID: 38651144 PMCID: PMC11033724 DOI: 10.3389/fonc.2024.1275330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. In colorectal cancer (CRC), it is involved in different processes including tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. However, conflicting data regarding Eph receptors in CRC, especially in its putative role as an oncogene or a suppressor gene, make the precise role of Eph-ephrin interaction confusing in CRC development. In this review, we provide an overview of the literature and highlight evidence that collaborates with these ambiguous roles of the Eph/ephrin system in CRC, as well as the molecular findings that represent promising therapeutic targets.
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Affiliation(s)
- João Figueira Scarini
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Moisés Willian Aparecido Gonçalves
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Reydson Alcides de Lima-Souza
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Luccas Lavareze
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Talita de Carvalho Kimura
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Ching-Chu Yang
- Department of Pathology, School of Medicine, University of Utah (UU), Salt Lake City, UT, United States
| | - Albina Altemani
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Fernanda Viviane Mariano
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Heloisa Prado Soares
- Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
| | - Gary Chris Fillmore
- Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
| | - Erika Said Abu Egal
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
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Garza Treviño EN, Quiroz Reyes AG, Rojas Murillo JA, de la Garza Kalife DA, Delgado Gonzalez P, Islas JF, Estrada Rodriguez AE, Gonzalez Villarreal CA. Cell Therapy as Target Therapy against Colon Cancer Stem Cells. Int J Mol Sci 2023; 24:ijms24098163. [PMID: 37175871 PMCID: PMC10179203 DOI: 10.3390/ijms24098163] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with properties, such as self-renewal, differentiation, and tumorigenicity. CSCs have been proposed as a plausible therapeutic target as they are responsible for tumor recurrence, metastasis, and conventional therapy resistance. Selectively targeting CSCs is a promising strategy to eliminate the propagation of tumor cells and impair overall tumor development. Recent research shows that several immune cells play a crucial role in regulating tumor cell proliferation by regulating different CSC maintenance or proliferation pathways. There have been great advances in cellular immunotherapy using T cells, natural killer (NK) cells, macrophages, or stem cells for the selective targeting of tumor cells or CSCs in colorectal cancer (CRC). This review summarizes the CRC molecular profiles that may benefit from said therapy and the main vehicles used in cell therapy against CSCs. We also discuss the challenges, limitations, and advantages of combining conventional and/or current targeted treatments in the late stages of CRC.
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Affiliation(s)
- Elsa N Garza Treviño
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Adriana G Quiroz Reyes
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Juan Antonio Rojas Murillo
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - David A de la Garza Kalife
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Paulina Delgado Gonzalez
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Jose F Islas
- Laboratorio de Terapia Celular, Departamento de Bioquímica y Medicina Molecular, Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Dr. José Eleuterio González 235, Monterrey 64460, Nuevo León, Mexico
| | - Ana Esther Estrada Rodriguez
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500. Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
| | - Carlos A Gonzalez Villarreal
- Departamento de Ciencias Básicas, Vicerrectoría de Ciencias de la Salud, Universidad de Monterrey, Ignacio Morones Prieto 4500. Jesus M. Garza, San Pedro Garza García 66238, Nuevo León, Mexico
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4
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Ji X, Ma H, Du Y. Role and mechanism of action of LAPTM4B in EGFR‑mediated autophagy (Review). Oncol Lett 2022; 23:109. [PMID: 35242237 DOI: 10.3892/ol.2022.13229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/17/2022] [Indexed: 12/09/2022] Open
Affiliation(s)
- Xiaokun Ji
- Department of Cytology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Hua Ma
- Department of Cytology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yun Du
- Department of Cytology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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Arai H, Millstein J, Loupakis F, Stintzing S, Wang J, Battaglin F, Kawanishi N, Jayachandran P, Soni S, Zhang W, Mumenthaler SM, Cremolini C, Heinemann V, Falcone A, Lenz HJ. Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer. Eur J Cancer 2021; 150:133-142. [PMID: 33901792 PMCID: PMC12047410 DOI: 10.1016/j.ejca.2021.03.048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/17/2021] [Accepted: 03/25/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes. RESULTS In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis. CONCLUSIONS Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.
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Affiliation(s)
- Hiroyuki Arai
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Joshua Millstein
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Fotios Loupakis
- Clinical and Experimental Oncology Department, Medical Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Sebastian Stintzing
- Medical Department, Division of Hematology, Oncology, and Tumour Immunology (CCM), Charité - Universitaetsmedizin, Berlin, Germany
| | - Jingyuan Wang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Natsuko Kawanishi
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Priya Jayachandran
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Shannon M Mumenthaler
- Lawrence J. Ellison Institute for Transformative Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Chiara Cremolini
- Department of Translational Medicine, Division of Medical Oncology, University of Pisa, Pisa, Italy
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Alfredo Falcone
- Department of Translational Medicine, Division of Medical Oncology, University of Pisa, Pisa, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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Usman RM, Razzaq F, Akbar A, Farooqui AA, Iftikhar A, Latif A, Hassan H, Zhao J, Carew JS, Nawrocki ST, Anwer F. Role and mechanism of autophagy-regulating factors in tumorigenesis and drug resistance. Asia Pac J Clin Oncol 2021; 17:193-208. [PMID: 32970929 DOI: 10.1111/ajco.13449] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/26/2020] [Indexed: 12/19/2022]
Abstract
A hallmark feature of tumorigenesis is uncontrolled cell division. Autophagy is regulated by more than 30 genes and it is one of several mechanisms by which cells maintain homeostasis. Autophagy promotes cancer progression and drug resistance. Several genes play important roles in autophagy-induced tumorigenesis and drug resistance including Beclin-1, MIF, HMGB1, p53, PTEN, p62, RAC3, SRC3, NF-2, MEG3, LAPTM4B, mTOR, BRAF and c-MYC. These genes alter cell growth, cellular microenvironment and cell division. Mechanisms involved in tumorigenesis and drug resistance include microdeletions, genetic mutations, loss of heterozygosity, hypermethylation, microsatellite instability and translational modifications at a molecular level. Disrupted or altered autophagy has been reported in hematological malignancies like lymphoma, leukemia and myeloma as well as multiple solid organ tumors like colorectal, hepatocellular, gall bladder, pancreatic, gastric and cholangiocarcinoma among many other malignancies. In addition, defects in autophagy also play a role in drug resistance in cancers like osteosarcoma, ovarian and lung carcinomas following treatment with drugs such as doxorubicin, paclitaxel, cisplatin, gemcitabine and etoposide. Therapeutic approaches that modulate autophagy are a novel future direction for cancer drug development that may help to prevent issues with disease progression and overcome drug resistance.
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Affiliation(s)
- Rana Muhammad Usman
- Department of Medicine, The University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Faryal Razzaq
- Foundation University Medical College, Islamabad, Pakistan
| | - Arshia Akbar
- Department of Medical Intensive Care, Holy Family Hospital, Rawalpindi, Pakistan
| | | | - Ahmad Iftikhar
- Department of Medicine, The University of Arizona, Tucson, AZ, USA
| | - Azka Latif
- Department of Medicine, Crieghton University, Omaha, NE, USA
| | - Hamza Hassan
- Department of Hematology & Medical Oncology, Boston University Medical Center, Boston, MA, USA
| | - Jianjun Zhao
- Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
| | - Jennifer S Carew
- Department of Medicine, The University of Arizona, Tucson, AZ, USA
| | | | - Faiz Anwer
- Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA
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Frank MH, Wilson BJ, Gold JS, Frank NY. Clinical Implications of Colorectal Cancer Stem Cells in the Age of Single-Cell Omics and Targeted Therapies. Gastroenterology 2021; 160:1947-1960. [PMID: 33617889 PMCID: PMC8215897 DOI: 10.1053/j.gastro.2020.12.080] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 11/30/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023]
Abstract
The cancer stem cell (CSC) concept emerged from the recognition of inherent tumor heterogeneity and suggests that within a given tumor, in analogy to normal tissues, there exists a cellular hierarchy composed of a minority of more primitive cells with enhanced longevity (ie, CSCs) that give rise to shorter-lived, more differentiated cells (ie, cancer bulk populations), which on their own are not capable of tumor perpetuation. CSCs can be responsible for cancer therapeutic resistance to conventional, targeted, and immunotherapeutic treatment modalities, and for cancer progression through CSC-intrinsic molecular mechanisms. The existence of CSCs in colorectal cancer (CRC) was first established through demonstration of enhanced clonogenicity and tumor-forming capacity of this cell subset in human-to-mouse tumor xenotransplantation experiments and subsequently confirmed through lineage-tracing studies in mice. Surface markers for CRC CSC identification and their prospective isolation are now established. Therefore, the application of single-cell omics technologies to CSC characterization, including whole-genome sequencing, RNA sequencing, and epigenetic analyses, opens unprecedented opportunities to discover novel targetable molecular pathways and hence to develop novel strategies for CRC eradication. We review recent advances in this field and discuss the potential implications of next-generation CSC analyses for currently approved and experimental targeted CRC therapies.
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Affiliation(s)
- Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;,Department of Dermatology, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts;,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts;,School of Medical and Health Sciences, Edith Cowan University, Perth, Western Australia, Australia
| | - Brian J. Wilson
- Transplant Research Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts;,Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts
| | - Jason S. Gold
- Department of Surgery, Veterans Affairs Boston Healthcare System, Boston, Massachusetts;,Department of Surgery, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - Natasha Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts;,Department of Medicine, Veterans Affairs Boston Healthcare System, Boston, Massachusetts;,Division of Genetics, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts
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8
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Gu XY, Jiang Y, Li MQ, Han P, Liu YL, Cui BB. Over-expression of EGFR regulated by RARA contributes to 5-FU resistance in colon cancer. Aging (Albany NY) 2020; 12:156-177. [PMID: 31896739 PMCID: PMC6977699 DOI: 10.18632/aging.102607] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 12/05/2019] [Indexed: 12/13/2022]
Abstract
A promising new strategy for cancer therapy is to target the autophagic pathway. However, comprehensive characterization of autophagy genes and their clinical relevance in cancer is still lacking. Here, we systematically characterized alterations of autophagy genes in multiple cancer lines by analyzing data from The Cancer Genome Atlas and CellMiner database. Interactions between autophagy genes and clinically actionable genes (CAGs) were identified by analyzing co-expression, protein-protein interactions (PPIs) and transcription factor (TF) data. A key subnetwork was identified that included 18 autophagy genes and 22 CAGs linked by 28 PPI pairs and 1 TF-target pair, which was EGFR targeted by RARA. Alterations in the expression of autophagy genes were associated with patient survival in multiple cancer types. RARA and EGFR were associated with worse survival in colorectal cancer patients. The regulatory role of EGFR in 5-FU resistance was validated in colon cancer cells in vivo and in vitro. EGFR contributed to 5-FU resistance in colon cancer cells through autophagy induction, and EGFR overexpression in 5-FU resistant colon cancer was regulated by RARA. The present study provides a comprehensive analysis of autophagy in different cancer cell lines and highlights the potential clinical utility of targeting autophagy genes.
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Affiliation(s)
- Xin-Yue Gu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, People's Republic of China
| | - Yang Jiang
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150040, People's Republic of China
| | - Ming-Qi Li
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, People's Republic of China
| | - Peng Han
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, People's Republic of China
| | - Yan-Long Liu
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, People's Republic of China
| | - Bin-Bin Cui
- Department of Colorectal Surgery, Harbin Medical University Cancer Hospital, Harbin 150040, People's Republic of China
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9
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Silva VR, Corrêa RS, Santos LDS, Soares MBP, Batista AA, Bezerra DP. A ruthenium-based 5-fluorouracil complex with enhanced cytotoxicity and apoptosis induction action in HCT116 cells. Sci Rep 2018; 8:288. [PMID: 29321581 PMCID: PMC5762908 DOI: 10.1038/s41598-017-18639-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Accepted: 12/14/2017] [Indexed: 12/27/2022] Open
Abstract
Combination of multifunctionalities into one compound is a rational strategy in medicinal chemical design, and have often been used with metallodrug-based compounds. In the present study, we synthesized a novel ruthenium-based 5-fluorouracil complex [Ru(5-FU)(PPh3)2(bipy)]PF6 (PPh3 = triphenylphosphine; and bipy = 2,2′-bipyridine) with enhanced cytotoxicity in different cancer cells, and assessed its apoptosis induction action in human colon carcinoma HCT116 cells. The complex was characterized by infrared, cyclic voltammetry, molar conductance measurements, elemental analysis, NMR experiments and X-ray crystallographic analysis. In both 2D and 3D cell culture models, the complex presented cytotoxicity to cancer cells more potent than 5-FU. A typical morphology of apoptotic cell death, increased internucleosomal DNA fragmentation, without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization and caspase-3 activation were observed in complex-treated HCT116 cells. Moreover, the pre-treatment with Z-DEVD-FMK, a caspase-3 inhibitor, reduced the apoptosis induced by the complex, indicating cell death by apoptosis through caspase-dependent and mitochondrial intrinsic pathways. The complex failed to induce reactive oxygen species production and DNA intercalation. In conclusion, the novel complex displays enhanced cytotoxicity to different cancer cells, and is able to induce caspase-mediated apoptosis in HCT116 cells.
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Affiliation(s)
| | - Rodrigo S Corrêa
- Department of Chemistry, Federal University of Ouro Preto, Ouro Preto, Minas Gerais, 35400-000, Brazil
| | - Luciano de Souza Santos
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil
| | - Milena Botelho Pereira Soares
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.,Center of Biotechnology and Cell therapy, Hospital São Rafael, Salvador, Bahia, 41253-190, Brazil
| | - Alzir Azevedo Batista
- Department of Chemistry, Federal University of São Carlos, São Carlos, São Paulo, 13561-901, Brazil
| | - Daniel Pereira Bezerra
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (IGM-FIOCRUZ/BA), Salvador, Bahia, 40296-710, Brazil.
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10
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McCubrey JA, Abrams SL, Lertpiriyapong K, Cocco L, Ratti S, Martelli AM, Candido S, Libra M, Murata RM, Rosalen PL, Lombardi P, Montalto G, Cervello M, Gizak A, Rakus D, Steelman LS. Effects of berberine, curcumin, resveratrol alone and in combination with chemotherapeutic drugs and signal transduction inhibitors on cancer cells-Power of nutraceuticals. Adv Biol Regul 2018; 67:190-211. [PMID: 28988970 DOI: 10.1016/j.jbior.2017.09.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 09/29/2017] [Indexed: 06/07/2023]
Abstract
Over the past fifty years, society has become aware of the importance of a healthy diet in terms of human fitness and longevity. More recently, the concept of the beneficial effects of certain components of our diet and other compounds, that are consumed often by different cultures in various parts of the world, has become apparent. These "healthy" components of our diet are often referred to as nutraceuticals and they can prevent/suppress: aging, bacterial, fungal and viral infections, diabetes, inflammation, metabolic disorders and cardiovascular diseases and have other health-enhancing effects. Moreover, they are now often being investigated because of their anti-cancer properties/potentials. Understanding the effects of various natural products on cancer cells may enhance their usage as anti-proliferative agents which may be beneficial for many health problems. In this manuscript, we discuss and demonstrate how certain nutraceuticals may enhance other anti-cancer drugs to suppress proliferation of cancer cells.
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Affiliation(s)
- James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
| | - Stephen L Abrams
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
| | - Kvin Lertpiriyapong
- Department of Comparative Medicine, Brody School of Medicine at East Carolina University, USA; Center of Comparative Medicine and Pathology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medicine and the Hospital for Special Surgery, New York City, New York, USA
| | - Lucio Cocco
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Stefano Ratti
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Alberto M Martelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Saverio Candido
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Massimo Libra
- Department of Biomedical and Biotechnological Sciences - Oncological, Clinical and General Pathology Section, University of Catania, Catania, Italy
| | - Ramiro M Murata
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA; Department of Foundational Sciences, School of Dental Medicine, East Carolina University, USA
| | - Pedro L Rosalen
- Department of Physiological Sciences, Piracicaba Dental School, State University of Campinas, Piracicaba, Brazil
| | - Paolo Lombardi
- Naxospharma, Via Giuseppe Di Vittorio 70, Novate Milanese 20026, Italy
| | - Giuseppe Montalto
- Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy; Consiglio Nazionale Delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Melchiorre Cervello
- Consiglio Nazionale Delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare "Alberto Monroy", Palermo, Italy
| | - Agnieszka Gizak
- Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Dariusz Rakus
- Department of Molecular Physiology and Neurobiology, Wroclaw University, Wroclaw, Poland
| | - Linda S Steelman
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA
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Sipos F, Székely H, Kis ID, Tulassay Z, Műzes G. Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer. World J Gastroenterol 2017; 23:8109-8119. [PMID: 29290648 PMCID: PMC5739918 DOI: 10.3748/wjg.v23.i46.8109] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 10/28/2017] [Accepted: 12/04/2017] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome (MetS), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. The IGF1R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from MetS who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic benefits could be achieved by inhibition of one of the key effectors of the IGF1R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1R modulation can initiate additional, sometimes unfavorable biologic effects.
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Affiliation(s)
- Ferenc Sipos
- 2nd Department of Internal Medicine, Semmelweis University, Budapest 1088, Hungary
| | - Hajnal Székely
- 2nd Department of Internal Medicine, Semmelweis University, Budapest 1088, Hungary
| | - Imre Dániel Kis
- Faculty of Medicine, Semmelweis University, Budapest 1088, Hungary
| | - Zsolt Tulassay
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest 1088, Hungary
| | - Györgyi Műzes
- 2nd Department of Internal Medicine, Semmelweis University, Budapest 1088, Hungary
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12
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Qian HR, Shi ZQ, Zhu HP, Gu LH, Wang XF, Yang Y. Interplay between apoptosis and autophagy in colorectal cancer. Oncotarget 2017; 8:62759-62768. [PMID: 28977986 PMCID: PMC5617546 DOI: 10.18632/oncotarget.18663] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 05/15/2017] [Indexed: 12/15/2022] Open
Abstract
Autophagy and apoptosis are two pivotal mechanisms in mediating cell survival and death. Cross-talk of autophagy and apoptosis has been documented in the tumorigenesis and progression of cancer, while the interplay between the two pathways in colorectal cancer (CRC) has not yet been comprehensively summarized. In this study, we outlined the basis of apoptosis and autophagy machinery firstly, and then reviewed the recent evidence in cellular settings or animal studies regarding the interplay between them in CRC. In addition, several key factors that modulate the cross-talk between autophagy and apoptosis as well as its significance in clinical practice were discussed. Understanding of the interplay between the cell death mechanisms may benefit the translation of CRC treatment from basic research to clinical use.
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Affiliation(s)
- Hao-Ran Qian
- Department of General Surgery, Institute of Minimally Invasive, Surgery of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, PR China
| | - Zhao-Qi Shi
- Department of General Surgery, Institute of Minimally Invasive, Surgery of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, PR China
| | - He-Pan Zhu
- Department of General Surgery, Institute of Minimally Invasive, Surgery of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, PR China
| | - Li-Hu Gu
- Department of General Surgery, Institute of Minimally Invasive, Surgery of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, PR China
| | - Xian-Fa Wang
- Department of General Surgery, Institute of Minimally Invasive, Surgery of Zhejiang University, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang, PR China
| | - Yi Yang
- Department of Pharmacology, Hangzhou Key Laboratory of Medical Neurobiology, School of Medicine, Hangzhou Normal University, Hangzhou 310036, Zhejiang, PR China
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