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1
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He C, He J. Metabolic reprogramming and signaling adaptations in anoikis resistance: mechanisms and therapeutic targets. Mol Cell Biochem 2025; 480:3315-3342. [PMID: 39821582 DOI: 10.1007/s11010-024-05199-3] [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: 11/17/2024] [Accepted: 12/20/2024] [Indexed: 01/19/2025]
Abstract
Anoikis, a form of programmed cell death triggered by detachment from the extracellular matrix (ECM), maintains tissue homeostasis by removing mislocalized or detached cells. Cancer cells, however, have evolved multiple mechanisms to evade anoikis under conditions of ECM detachment, enabling survival and distant metastasis. Studies have identified differentially expressed proteins between suspended and adherent cancer cells, revealing that key metabolic and signaling pathways undergo significant alterations during the acquisition of anoikis resistance. This review explores the regulatory roles of epithelial-mesenchymal transition, cancer stem cell characteristics, metabolic reprogramming, and various signaling pathway alterations in promoting anoikis resistance. And the corresponding reagents and non-coding RNAs that target the aforementioned pathways are reviewed. By discussing the regulatory mechanisms that facilitate anoikis resistance in cancer cells, this review aims to shed light on potential strategies for inhibiting tumor progression and preventing metastasis.
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Affiliation(s)
- Chao He
- Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Jie He
- Department of Nursing, Operating Room, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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2
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Baghaie L, Bunsick DA, Aucoin EB, Skapinker E, Yaish AM, Li Y, Harless WW, Szewczuk MR. Pro-Inflammatory Cytokines Transactivate Glycosylated Cytokine Receptors on Cancer Cells to Induce Epithelial-Mesenchymal Transition to the Metastatic Phenotype. Cancers (Basel) 2025; 17:1234. [PMID: 40227834 PMCID: PMC11988151 DOI: 10.3390/cancers17071234] [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: 02/26/2025] [Revised: 03/27/2025] [Accepted: 04/03/2025] [Indexed: 04/15/2025] Open
Abstract
Background/Objectives: The significance of cytokine signaling on cancer progression and metastasis has raised interest in cancer research over the last few decades. Here, we analyzed the effects of three cytokines that we previously reported are significantly upregulated rapidly after the surgical removal of primary breast, colorectal, and prostate cancer. We also investigated the regulation of their cognate receptors. Methods: All experiments were conducted using the PANC-1, SW620, and MCF-7 cell lines, treated with three different cytokines (TGF-β1, HGF, and IL-6). The effect of these cytokines on the expression of epithelial-mesenchymal transition (EMT) cell surface markers and neuraminidase-1 activity was measured via fluorescent microscopy and image analysis software. Results: The findings show that these cytokines increase the expression of mesenchymal markers while reducing epithelial markers, corresponding to the EMT process. A strong link between cytokine receptor signaling and the Neu-1-MMP-9-GPCR crosstalk was identified, suggesting that cytokine receptor binding leads to increased Neu-1 activity and subsequent signaling pathway activation. Oseltamivir phosphate (OP) prevented sialic acid hydrolysis by neuraminidase-1 (Neu-1), leading to the downregulation of these signaling cascades. Conclusions: In concert with the previous work revealing the role of Neu-1 in regulating other glycosylated receptors implicated in cancer cell proliferation and EMT, targeting Neu-1 may provide effective treatment against a variety of malignancies. Most significantly, the treatment of patients with specific inhibitors of Neu-1 soon after primary cancer surgery may improve our ability to cure early-stage cancer by inhibiting the EMT process and disrupting the ability of any residual cancer cell population to metastasize.
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Affiliation(s)
- Leili Baghaie
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (L.B.); (D.A.B.)
| | - David A. Bunsick
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (L.B.); (D.A.B.)
| | - Emilyn B. Aucoin
- Faculty of Science, Biology (Biomedical Science), York University, Toronto, ON M3J 1P3, Canada;
| | - Elizabeth Skapinker
- Faculty of Arts and Science, Queen’s University, Kingston, ON K7L 3N9, Canada; (E.S.); (Y.L.)
| | | | - Yunfan Li
- Faculty of Arts and Science, Queen’s University, Kingston, ON K7L 3N9, Canada; (E.S.); (Y.L.)
| | | | - Myron R. Szewczuk
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (L.B.); (D.A.B.)
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3
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Bunsick DA, Baghaie L, Li Y, Yaish AM, Aucoin EB, Skapinker E, Aldbai R, Szewczuk MR. Synthetic CB1 Cannabinoids Promote Tunneling Nanotube Communication, Cellular Migration, and Epithelial-Mesenchymal Transition in Pancreatic PANC-1 and Colorectal SW-620 Cancer Cell Lines. Cells 2025; 14:71. [PMID: 39851499 PMCID: PMC11763365 DOI: 10.3390/cells14020071] [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: 09/18/2024] [Revised: 12/19/2024] [Accepted: 01/03/2025] [Indexed: 01/26/2025] Open
Abstract
Metastasizing cancer cells surreptitiously can adapt to metabolic activity during their invasion. By initiating their communications for invasion, cancer cells can reprogram their cellular activities to initiate their proliferation and migration and uniquely counteract metabolic stress during their progression. During this reprogramming process, cancer cells' metabolism and other cellular activities are integrated and mutually regulated by tunneling nanotube communications to alter their specific metabolic functional drivers of tumor growth and progression. Here, we investigated the in vitro effects of the synthetic CB1 cannabinoids AM-404, arvanil, and olvanil on human pancreatic PANC-1 and colorectal SW-620 cancer cell lines to understand further cellular behaviors and the potential risks of their use in cancer therapy. For the first time, the synthetic CB1 cannabinoids AM-404, arvanil, and olvanil significantly altered cancer cells in forming missile-like shapes to induce tunneling nanotube (TNT) communications in PANC-1 cells. Oseltamivir phosphate (OP) significantly prevented TNT formation. To assess the key survival pathways critical for pancreatic cancer progression, we used the AlamarBlue assay to determine synthetic CB1 cannabinoids to induce the cell's metabolic viability drivers to stage migratory intercellular communication. The synthetic CB1 cannabinoids significantly increased cell viability compared to the untreated control for PANC-1 and SW-620 cells, and this response was significantly reduced with the NMBR inhibitor BIM-23127, neuraminidase-1 inhibitor OP, and MMP-9 inhibitor (MMP-9i). CB1 cannabinoids also significantly increased N-cadherin and decreased E-cadherin EMT markers compared to the untreated controls, inducing the process of metastatic phenotype for invasion. BIM-23127, MMP9i, and OP significantly inhibited CB1 agonist-induced NFκB-dependent secretory alkaline phosphatase (SEAP) activity. To confirm this concept, we investigated the migratory invasiveness of PANC-1 and SW-620 cancer cells treated with the synthetic CB1 cannabinoids AM-404, arvanil, and olvanil in a scratch wound assay. CB1 cannabinoids significantly induced the rate of migration and invasiveness of PANC-1 cancer cells, whereas they had minimal effect on the rate of migration of already metastatic SW-620 cancer cells. Interestingly, olvanil-treated SW-620 cells significantly enhanced the migration rate and invasiveness of these cells. The data support the cellular and molecular mechanisms of the synthetic CB1 cannabinoids, orchestrating intercellular conduits to enhance metabolic drivers to stage migratory intercellular communication in pancreatic cancer cells.
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Affiliation(s)
- David A. Bunsick
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (D.A.B.); (L.B.); (R.A.)
| | - Leili Baghaie
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (D.A.B.); (L.B.); (R.A.)
| | - Yunfan Li
- Faculty of Arts and Science, Queen’s University, Kingston, ON K7L 3N9, Canada; (Y.L.); (E.S.)
| | | | - Emilyn B. Aucoin
- Faculty of Science, Biology (Biomedical Science), York University, Toronto, ON M3J 1P3, Canada;
| | - Elizabeth Skapinker
- Faculty of Arts and Science, Queen’s University, Kingston, ON K7L 3N9, Canada; (Y.L.); (E.S.)
| | - Rashelle Aldbai
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (D.A.B.); (L.B.); (R.A.)
| | - Myron R. Szewczuk
- Department of Biomedical & Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada; (D.A.B.); (L.B.); (R.A.)
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4
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Ruan F, Ruan Y, Gu H, Sun J, Chen Q. Clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis. Am J Physiol Cell Physiol 2024; 327:C884-C900. [PMID: 39140602 DOI: 10.1152/ajpcell.00310.2024] [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: 05/10/2024] [Revised: 07/18/2024] [Accepted: 08/05/2024] [Indexed: 08/15/2024]
Abstract
Chemotherapy resistance to colon cancer is an unavoidable obstacle in the clinical management of the disease. Clitocine, an adenosine analog, played a significant role in the chemosensitivity of human colon cancer cells by promoting myeloid cell leukemia 1 (MCL-1) protein degradation. However, the detailed mechanism remains to be further elucidated. We found that clitocine upregulates the expression of F-box and WD repeat domain containing 7 (FBXW7), a ubiquitin ligase involved in the MCL-1 degradation. Transcriptome sequencing analysis revealed that clitocine significantly inhibits the cyclic adenosine monophosphate (cAMP) and extracellular regulated protein kinases (ERK) downstream signaling pathways in colon cancer cells, thereby enhancing FBXW7 expression and subsequently promoting the ubiquitination degradation of MCL-1 protein. We verified that clitocine regulated intracellular cAMP levels by competitive binding with the adenosine receptor A2B. A molecular docking assay also verified the binding relationship. By decreasing intracellular cAMP levels, clitocine blocks the activation of downstream signaling pathways, which ultimately enhances the drug sensitivity of colon cancer cells through increased FBXW7 expression due to the inhibition of its promoter DNA methylation. Both knockout of the adenosine receptor A2B and Br-cAMP treatment can effectively attenuate the function of clitocine in vitro and in vivo. This study clarified that clitocine enhanced the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis, providing further knowledge of the clinical application for clitocine.NEW & NOTEWORTHY Our study found that clitocine enhances the drug sensitivity of colon cancer cells by promoting FBXW7-mediated MCL-1 degradation via inhibiting the A2B/cAMP/ERK axis.
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Affiliation(s)
- Feng Ruan
- Department of Emergency Medicine, Second Affiliated Hospital Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Yanyun Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People's Republic of China
| | - Huamin Gu
- Department of Pathology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People's Republic of China
| | - Jianguo Sun
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People's Republic of China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, People's Republic of China
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Verhagen MP, Xu T, Stabile R, Joosten R, Tucci FA, van Royen M, Trerotola M, Alberti S, Sacchetti A, Fodde R. The SW480 cell line as a model of resident and migrating colon cancer stem cells. iScience 2024; 27:110658. [PMID: 39246444 PMCID: PMC11379671 DOI: 10.1016/j.isci.2024.110658] [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: 03/13/2024] [Revised: 06/27/2024] [Accepted: 07/31/2024] [Indexed: 09/10/2024] Open
Abstract
Intra-tumor heterogeneity, i.e., the presence of diverse cell types and subpopulations within tumors, presents a significant obstacle in cancer treatment due to its negative consequences for resistance to therapy and disease recurrence. However, the mechanisms that underlie intra-tumor heterogeneity and result in the plethora of different cancer cells within a single lesion remain poorly understood. Here, we leverage the SW480 cell line as a model system to investigate the molecular and functional diversity of colon cancer cells. Through a combination of fluorescence-activated cell sorting (FACS) analysis and transcriptomic profiling, we identified three distinct subpopulations, namely resident cancer stem cells (rCSCs), migratory CSCs (mCSCs), and high-relapse cells (HRCs). These subpopulations show varying Wnt signaling levels and gene expression profiles mirroring their stem-like and functional properties. Examination of publicly available spatial transcriptomic data confirms the presence of these subpopulations in patient-derived cancers and reveals their distinct spatial distribution relative to the tumor microenvironment.
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Affiliation(s)
- Mathijs P Verhagen
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Tong Xu
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Roberto Stabile
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Rosalie Joosten
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Francesco A Tucci
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Martin van Royen
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Marco Trerotola
- Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Chieti, Italy
| | - Saverio Alberti
- Department of Biomedical Sciences, University of Messina, Messina, Italy
| | - Andrea Sacchetti
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Riccardo Fodde
- Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands
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6
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Hsu YC, Luo CW, Chang SJ, Lai CY, Yang YT, Chen YZ, Liu WT, Wu CC, Sun CK, Hou MF, Pan MR. Targeting Bmi1 for Enhancing Anoikis Sensitivity and Inhibiting Metastasis in Colorectal Cancer. Cancer Genomics Proteomics 2024; 21:523-532. [PMID: 39191496 PMCID: PMC11363924 DOI: 10.21873/cgp.20469] [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: 06/30/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024] Open
Abstract
BACKGROUND/AIM Patients diagnosed with advanced metastatic colorectal cancer (CRC) confront a bleak prognosis characterized by low survival rates. Anoikis, the programmed apoptosis resistance exhibited by metastatic cancer cells, is a crucial factor in this scenario. MATERIALS AND METHODS We employed bulk flow cytometry and RT-qPCR assays, conducted in vivo experiments with mice and zebrafish, and analyzed patient tissues to examine the effects of the B cell-specific Moloney murine leukemia virus insertion site 1 (Bmi1)-midkine (MDK) axis on the cellular response to anoikis. Bmi1 is pivotal in tumorigenesis. This study elucidated the involvement of Bmi1 in conferring anoikis resistance in CRC and explored its downstream targets associated with metastasis. RESULTS Elevated levels of Bmi1 expression correlated with distant metastasis in CRC. Suppression of Bmi1 significantly diminished the metastatic potential of CRC cells. Inhibition of Bmi1 led to an increase in the proportion of apoptotic SW620 cells detached from the matrix. This effect was further enhanced by the addition of irinotecan, a topoisomerase I inhibitor. Furthermore, Bmi1 was found to synergize with MDK in modulating CRC viability, with consistent expression patterns observed in in vivo models and clinical tissue specimens. In summary, Bmi1 acted as a regulator of CRC metastatic capability by conferring anoikis resistance. Additionally, it collaborated with MDK to facilitate invasion and distant metastasis. CONCLUSION Targeting Bmi1 may offer a promising adjunctive therapeutic strategy when administering traditional chemotherapy regimens to patients with advanced CRC.
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Affiliation(s)
- Yin-Chou Hsu
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung, Taiwan, R.O.C
- School of Medicine for International Student, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Chi-Wen Luo
- Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C
- Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, R.O.C
| | - Shu-Jyuan Chang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Chiao-Ying Lai
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Yu-Tzu Yang
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Yi-Zi Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Wang-Ta Liu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Chun-Chieh Wu
- Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
| | - Cheuk-Kwan Sun
- School of Medicine for International Student, I-Shou University, Kaohsiung, Taiwan, R.O.C
- Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung, Taiwan, R.O.C
| | - Ming-Feng Hou
- Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.;
| | - Mei-Ren Pan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.;
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, R.O.C
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Wang Y, Zeng H, Li L, Liu J, Lin J, Bie Y, Wang S, Cheng X, Nashun B, Yao Y, Hu X, Zhao Y. Pokemon inhibits Bim transcription to promote the proliferation, anti-anoikis, invasion, histological grade, and dukes stage of colorectal neoplasms. J Cancer Res Clin Oncol 2024; 150:380. [PMID: 39095579 PMCID: PMC11297103 DOI: 10.1007/s00432-024-05904-1] [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: 05/14/2024] [Accepted: 07/20/2024] [Indexed: 08/04/2024]
Abstract
PURPOSE This study aims to determine whether Pokemon regulates Bim activity in colorectal carcinoma (CRC) carcinogenesis. METHODS Clinical tissue samples were analyzed to detect the expression and clinicopathological significance of Pokemon and Bim in CRC. Proliferation, apoptosis, and invasion assays were conducted to identify the regulatory effect of Pokemon on Bim. The combined treatment effects of Pokemon knockdown and diamminedichloroplatinum (DDP) were also examined. RESULTS Immunohistochemical analysis of 80 samples of colorectal epithelia (CRE), 80 cases of colorectal adenoma (CRA), and 160 of CRC samples revealed protein expression rates of 23.8%, 38.8%, and 70.6% for Pokemon, and 88.8%, 73.8%, and 31.9% for Bim, respectively. A significant negative correlation was observed between Pokemon and Bim expression across the CRE, CRA, and CRC lesion stages. In CRC, higher Pokemon and lower Bim expression correlated with higher histological grades, advanced Dukes stages, and increased cancer invasion. In both LoVo and HCT116 cells, overexpression of Pokemon significantly reduced Bim expression, leading to increased proliferation, resistance to anoikis, and cell invasion. Additionally, Pokemon overexpression significantly decreased DDP-induced Bim expression, reduction of anti-apoptosis and invasion, whereas Pokemon knockdown resulted in the opposite effects. CONCLUSION These findings suggest that Pokemon inhibits Bim transcription, thereby promoting CRC proliferation, resistance to apoptosis, invasion, and advancing histological grade and Dukes staging. Pokemon knockdown enhances the therapeutic efficacy of DDP in the treatment of CRC.
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Affiliation(s)
- Yan Wang
- Microbiology and Immunology Department, Guangdong Medical University, Dongguan, 523808, China
- Pathology Department of The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523713, China
| | - Huiling Zeng
- Microbiology and Immunology Department, Guangdong Medical University, Dongguan, 523808, China
| | - Li Li
- Pathology Department, Huizhou Health Sciences Polytechnic, Huizhou, 516007, China
| | - Jizhen Liu
- Animal Center of Guangdong Medical University, Guangdong Medical University, Dongguan, 523808, China
| | - Jiantao Lin
- Key Laboratory of Molecular Diagnosis, Guangdong Medical University, Dongguan, 523808, China
| | - Yanhong Bie
- Pathology Department of The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523713, China
| | - Sen Wang
- Animal Center of Guangdong Medical University, Guangdong Medical University, Dongguan, 523808, China
| | - Xiaoguang Cheng
- Key Laboratory of Molecular Diagnosis, Guangdong Medical University, Dongguan, 523808, China
| | - Bayaer Nashun
- Animal Center of Guangdong Medical University, Guangdong Medical University, Dongguan, 523808, China
| | - Yunhong Yao
- Pathology Department of The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523713, China
| | - Xinrong Hu
- Pathology Department of The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523713, China.
| | - Yi Zhao
- Microbiology and Immunology Department, Guangdong Medical University, Dongguan, 523808, China.
- Pathology Department of The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, 523713, China.
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Azbazdar Y, Sosa EA, Monka J, Kurmangaliyev YZ, Tejeda-Muñoz N. Interactions between genistein and Wnt pathway in colon adenocarcinoma and early embryos. Heliyon 2024; 10:e32243. [PMID: 38947477 PMCID: PMC11214441 DOI: 10.1016/j.heliyon.2024.e32243] [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: 02/13/2024] [Revised: 04/30/2024] [Accepted: 05/30/2024] [Indexed: 07/02/2024] Open
Abstract
The Wnt signaling pathway is one of the most ancient and pivotal signaling cascades, governing diverse processes in development and cancer regulation. Within the realm of cancer treatment, genistein emerges as a promising candidate due to its multifaceted modulation of various signaling pathways, including the Wnt pathway. Despite promising preclinical studies, the precise mechanisms underlying genistein's therapeutic effects via Wnt modulation remain elusive. In this study, we unveil novel insights into the therapeutic mechanisms of genistein by elucidating its inhibitory effects on Wnt signaling through macropinocytosis. Additionally, we demonstrate its capability to curtail cell growth, proliferation, and lysosomal activity in the SW480 colon adenocarcinoma cell model. Furthermore, our investigation extends to the embryonic context, where genistein influences gene regulatory networks governed by endogenous Wnt pathways. Our findings shed light on the intricate interplay between genistein, Wnt signaling, membrane trafficking, and gene regulation, paving the way for further exploration of genistein's therapeutic potential in cancer treatment strategies.
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Affiliation(s)
- Yagmur Azbazdar
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, 90095-1662, USA
| | - Eric A. Sosa
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Julia Monka
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, 90095-1662, USA
| | | | - Nydia Tejeda-Muñoz
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, 90095-1662, USA
- Department of Oncology Science, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
- OU Health Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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9
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Zhang W, Huang Z, Xiao Z, Wang H, Liao Q, Deng Z, Wu D, Wang J, Li Y. NF-κB downstream miR-1262 disturbs colon cancer cell malignant behaviors by targeting FGFR1. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1819-1832. [PMID: 37867436 PMCID: PMC10686795 DOI: 10.3724/abbs.2023235] [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: 12/16/2022] [Accepted: 03/23/2023] [Indexed: 10/24/2023] Open
Abstract
Despite substantial advancements in screening, surgery, and chemotherapy, colorectal cancer remains the second most lethal form of the disease. Nuclear factor kappa B (NF-κB) signaling is a critical driver facilitating the malignant transformation of chronic inflammatory bowel diseases. In this study, deregulated miRNAs that could play a role in colon cancer are analyzed and investigated for specific functions in vitro using cancer cells and in vivo using a subcutaneous xenograft model. miRNA downstream targets are analyzed, and predicted binding and regulation are verified. miR-1262, an antitumor miRNA, is downregulated in colon cancer tissue samples and cell lines. miR-1262 overexpression suppresses colon cancer malignant behaviors in vitro and tumor development and metastasis in a subcutaneous xenograft model and a lung metastasis mouse model in vivo. miR-1262 directly targets fibroblast growth factor receptor 1 (FGFR1) and inhibits FGFR1 expression. FGFR1 overexpression shows oncogenic functions through the regulation of cancer cell proliferation, invasion, and migration; when cotransfected, lv-FGFR1 partially attenuates the antitumor effects of agomir-1262. NF-κB binds to the miR-1262 promoter region and inhibits transcription activity. The NF-κB inhibitor CAPE exerts antitumor effects; miR-1262 inhibition partially reverses CAPE effects on colon cancer cells. Conclusively, miR-1262 serves as an antitumor miRNA in colon cancer by targeting FGFR1. The NF-κB/miR-1262/FGFR1 axis modulates colon cancer cell phenotypes, including proliferation, invasion, and migration.
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Affiliation(s)
- Weilin Zhang
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhou510080China
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
- Department of General SurgeryHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Zhongcheng Huang
- Department of General SurgeryHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Zhigang Xiao
- Department of General SurgeryHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Hui Wang
- Department of Cardiovascular MedicineHunan Provincial People’s Hospital (The First Affiliated Hospital of Hunan Normal University)Changsha410005China
| | - Qianchao Liao
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Zhengru Deng
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Deqing Wu
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Junjiang Wang
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
| | - Yong Li
- The Second School of Clinical MedicineSouthern Medical UniversityGuangzhou510080China
- Department of Gastrointestinal SurgeryDepartment of General SurgeryGuangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou510080China
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Wijewantha N, Sane S, Eikanger M, Antony RM, Potts RA, Lang L, Rezvani K, Sereda G. Enhancing Anti-Tumorigenic Efficacy of Eugenol in Human Colon Cancer Cells Using Enzyme-Responsive Nanoparticles. Cancers (Basel) 2023; 15:cancers15041145. [PMID: 36831488 PMCID: PMC9953800 DOI: 10.3390/cancers15041145] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/06/2023] [Accepted: 02/07/2023] [Indexed: 02/17/2023] Open
Abstract
This study is focused on the selective delivery and release of the plant-based anticancer compound eugenol (EUG) in colorectal cancer cells (CRC). EUG is an apoptotic and anti-growth compound in diverse malignant tumors, including CRC. However, EUG's rapid metabolization, excretion, and side effects on normal cells at higher dosages are major limitations of its therapeutic potential. To address this problem, we developed a "smart" enzyme-responsive nanoparticle (eNP) loaded with EUG that exposes tumors to a high level of the drug while keeping its concentration low among healthy cells. We demonstrated that EUG induces apoptosis in CRC cells irrespective of their grades in a dose- and time-dependent manner. EUG significantly decreases cancer cell migration, invasion, and the population of colon cancer stem cells, which are key players in tumor metastasis and drug resistance. The "smart" eNPs-EUG show a high affinity to cancer cells with rapid internalization with no affinity toward normal colon epithelial cells. NPs-EUG enhanced the therapeutic efficacy of EUG measured by a cell viability assay and showed no toxicity effect on normal cells. The development of eNPs-EUG is a promising strategy for innovative anti-metastatic therapeutics.
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Affiliation(s)
- Nisitha Wijewantha
- Department of Chemistry, The University of South Dakota, 414 E. Clark Street, Vermillion, SD 57069, USA
| | - Sanam Sane
- Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD 57069, USA
| | - Morgan Eikanger
- Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD 57069, USA
| | - Ryan M. Antony
- Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD 57069, USA
| | - Rashaun A. Potts
- Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD 57069, USA
| | - Lydia Lang
- Department of Chemistry, The University of South Dakota, 414 E. Clark Street, Vermillion, SD 57069, USA
| | - Khosrow Rezvani
- Division of Basic Biomedical Sciences, Sanford School of Medicine, The University of South Dakota, 414 E. Clark Street, Lee Medical Building, Vermillion, SD 57069, USA
- Correspondence: (K.R.); (G.S.)
| | - Grigoriy Sereda
- Department of Chemistry, The University of South Dakota, 414 E. Clark Street, Vermillion, SD 57069, USA
- Correspondence: (K.R.); (G.S.)
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11
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Du Q, Liu S, Dong K, Cui X, Luo J, Geller DA. Downregulation of iNOS/NO Promotes Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer. Mol Cancer Res 2023; 21:102-114. [PMID: 36306210 PMCID: PMC9890133 DOI: 10.1158/1541-7786.mcr-22-0509] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/28/2022] [Accepted: 10/26/2022] [Indexed: 02/06/2023]
Abstract
Metastasis is the major cause of cancer-related death in patients with colorectal cancer. Although inducible nitric oxide synthase (iNOS) is a crucial regulator of cancer development and progression, its roles in epithelial-mesenchymal transition (EMT) and the pathogenesis of metastatic colorectal cancer have not been fully investigated. Primary colorectal cancer and liver metastatic tissue specimens were analyzed showing 90% of liver metastatic colorectal cancer with reduced expressions of iNOS compared with 6% of primary colorectal cancer. The Cancer Genome Atlas database analyses via cBioPortal reveal that mRNA expression of iNOS negatively correlated with selected EMT markers in colorectal cancer in a cancer type-dependent manner. The transcriptomic profiling (RNA sequencing data) indicates that iNOS knockdown in SW480 colorectal cancer cells induced an EMT program with upregulated expression of selected stem-cell markers. iNOS knockdown did not alter E-cadherin mRNA expression but re-localized it from membrane to cytoplasm through iNOS-GATA4-Crb2-E-cadherin pathway. iNOS knockdown induced a change in cell morphology, and promoted cell invasion and migration in vitro, and metastasis in vivo. IMPLICATIONS iNOS downregulation-induced pathway networks mediate the EMT program and metastasis. As an EMT inducer, the reduced-iNOS may serve as a potential therapeutic target for patients with colorectal cancer.
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Affiliation(s)
- Qiang Du
- Department of Surgery, Thomas E. Starzl Transplant Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Silvia Liu
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Kun Dong
- Department of Surgery, Thomas E. Starzl Transplant Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiao Cui
- Department of Surgery, Thomas E. Starzl Transplant Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Surgery, The Second Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jing Luo
- Department of Surgery, Thomas E. Starzl Transplant Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
- Department of Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - David A. Geller
- Department of Surgery, Thomas E. Starzl Transplant Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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12
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Roles of anoikis in colorectal cancer therapy and the assessment of anoikis-regulatory molecules as therapeutic targets. Pathol Res Pract 2023; 241:154256. [PMID: 36455367 DOI: 10.1016/j.prp.2022.154256] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 11/21/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
Colorectal cancer (CRC) is a deadly malignancy and therapeutic approaches for CRC are evolving every day. Anoikis is a key mechanism for programmed cell death of cancer cells that undergo anchorage-independent growth at a different matrix than the one which is expected. Yet, anoikis is a less studied mechanism of cell death in comparison to other mechanisms such as apoptosis. Relating to this, resistance to anoikis among cancer cells remains critical for improved metastasis and survival in a new environment evading anoikis. Since CRC cells have the ability to metastasize from proximal sites to secondary organs such as liver and promote cancer in those distant sites, a clear knowledge of the mechanisms essential for anchorage-independent growth and subsequent metastasis is necessary to counteract CRC progression and spread. Therefore, the identification of novel drug candidates and studying the roles of anoikis in assisting CRC therapy using such drugs can prevent anchorage-independent cancer cell growth. Additionally, the identification of novel biomarkers or therapeutic targets seems essential for implementing superior therapy, impeding relapse among malignant cells and improving the survival rate of clinical patients. As there are no reviews published on this topic till date, anoikis as a mechanism of cell death and its therapeutic roles in CRC are discussed in this review. In addition, several molecules were identified as therapeutic targets for CRC.
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13
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Dukel M. Combination of naringenin and epicatechin sensitizes colon carcinoma cells to anoikis via regulation of the epithelial–mesenchymal transition (EMT). Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00317-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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14
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López-Cortés R, Muinelo-Romay L, Fernández-Briera A, Gil-Martín E. Inhibition of α(1,6)fucosyltransferase: Effects on Cell Proliferation, Migration, and Adhesion in an SW480/SW620 Syngeneic Colorectal Cancer Model. Int J Mol Sci 2022; 23:ijms23158463. [PMID: 35955598 PMCID: PMC9369121 DOI: 10.3390/ijms23158463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/01/2023] Open
Abstract
The present study explored the impact of inhibiting α(1,6)fucosylation (core fucosylation) on the functional phenotype of a cellular model of colorectal cancer (CRC) malignization formed by the syngeneic SW480 and SW620 CRC lines. Expression of the FUT8 gene encoding α(1,6)fucosyltransferase was inhibited in tumor line SW480 by a combination of shRNA-based antisense knockdown and Lens culinaris agglutinin (LCA) selection. LCA-resistant clones were subsequently assayed in vitro for proliferation, migration, and adhesion. The α(1,6)FT-inhibited SW480 cells showed enhanced proliferation in adherent conditions, unlike their α(1,6)FT-depleted SW620 counterparts, which displayed reduced proliferation. Under non-adherent conditions, α(1,6)FT-inhibited SW480 cells also showed greater growth capacity than their respective non-targeted control (NTC) cells. However, cell migration decreased in SW480 after FUT8 knockdown, while adhesion to EA.hy926 cells was significantly enhanced. The reported results indicate that the FUT8 knockdown strategy with subsequent selection for LCA-resistant clones was effective in greatly reducing α(1,6)FT expression in SW480 and SW620 CRC lines. In addition, α(1,6)FT impairment affected the proliferation, migration, and adhesion of α(1,6)FT-deficient clones SW480 and SW620 in a tumor stage-dependent manner, suggesting that core fucosylation has a dynamic role in the evolution of CRC.
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Affiliation(s)
- Rubén López-Cortés
- Doctoral Program in Methods and Applications in Life Sciences, Faculty of Biology, Campus Lagoas-Marcosende, Universidade de Vigo, 36310 Vigo, Spain;
| | - Laura Muinelo-Romay
- Liquid Biopsy Analysis Unit, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), CIBERONC, Travesía da Choupana, 15706 Santiago de Compostela, Spain;
| | - Almudena Fernández-Briera
- Department of Biochemistry, Genetics and Immunology, Faculty of Biology, Campus Lagoas-Marcosende, Universidade de Vigo, 36310 Vigo, Spain;
| | - Emilio Gil-Martín
- Department of Biochemistry, Genetics and Immunology, Faculty of Biology, Campus Lagoas-Marcosende, Universidade de Vigo, 36310 Vigo, Spain;
- Correspondence: ; Tel.: +34-(986)-812-570
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15
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Koliqi R, Grapci AD, Selmani PB, Uskoković V. Gene Expression Effects of the Delivery of SN-38 via Poly(D-L-lactide-co-caprolactone) Nanoparticles Comprising Dense and Collapsed Poloxamer Coronae. J Pharm Innov 2022. [DOI: 10.1007/s12247-022-09672-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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16
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Almaimani RA, Aslam A, Ahmad J, El-Readi MZ, El-Boshy ME, Abdelghany AH, Idris S, Alhadrami M, Althubiti M, Almasmoum HA, Ghaith MM, Elzubeir ME, Eid SY, Refaat B. In Vivo and In Vitro Enhanced Tumoricidal Effects of Metformin, Active Vitamin D 3, and 5-Fluorouracil Triple Therapy against Colon Cancer by Modulating the PI3K/Akt/PTEN/mTOR Network. Cancers (Basel) 2022; 14:1538. [PMID: 35326689 PMCID: PMC8946120 DOI: 10.3390/cancers14061538] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 12/21/2022] Open
Abstract
Chemoresistance to 5-fluorouracil (5-FU) is common during colorectal cancer (CRC) treatment. This study measured the chemotherapeutic effects of 5-FU, active vitamin D3 (VD3), and/or metformin single/dual/triple regimens as complementary/alternative therapies. Ninety male mice were divided into: negative and positive (PC) controls, and 5-FU, VD3, Met, 5-FU/VD3, 5-FU/Met, VD3/Met, and 5-FU/VD3/Met groups. Treatments lasted four weeks following CRC induction by azoxymethane. Similar regimens were also applied in the SW480 and SW620 CRC cell lines. The PC mice had abundant tumours, markedly elevated proliferation markers (survivin/CCND1) and PI3K/Akt/mTOR, and reduced p21/PTEN/cytochrome C/caspase-3 and apoptosis. All therapies reduced tumour numbers, with 5-FU/VD3/Met being the most efficacious regimen. All protocols decreased cell proliferation markers, inhibited PI3K/Akt/mTOR molecules, and increased proapoptotic molecules with an apoptosis index, and 5-FU/VD3/Met revealed the strongest effects. In vitro, all therapies equally induced G1 phase arrest in SW480 cells, whereas metformin-alone showed maximal SW620 cell numbers in the G0/G1 phase. 5-FU/Met co-therapy also showed the highest apoptotic SW480 cell numbers (13%), whilst 5-FU/VD3/Met disclosed the lowest viable SW620 cell percentages (81%). Moreover, 5-FU/VD3/Met revealed maximal inhibitions of cell cycle inducers (CCND1/CCND3), cell survival (BCL2), and the PI3K/Akt/mTOR molecules alongside the highest expression of cell cycle inhibitors (p21/p27), proapoptotic markers (BAX/cytochrome C/caspase-3), and PTEN in both cell lines. In conclusion, metformin monotherapy was superior to VD3, whereas the 5-FU/Met protocol showed better anticancer effects relative to the other dual therapies. However, the 5-FU/VD3/Met approach displayed the best in vivo and in vitro tumoricidal effects related to cell cycle arrest and apoptosis, justifiably by enhanced modulations of the PI3K/PTEN/Akt/mTOR pathway.
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Affiliation(s)
- Riyad Adnan Almaimani
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; (R.A.A.); (M.Z.E.-R.); (M.A.); (M.E.E.); (S.Y.E.)
| | - Akhmed Aslam
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
| | - Jawwad Ahmad
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
| | - Mahmoud Zaki El-Readi
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; (R.A.A.); (M.Z.E.-R.); (M.A.); (M.E.E.); (S.Y.E.)
- Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit 71524, Egypt
| | - Mohamed E. El-Boshy
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
- Clinical Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt
| | - Abdelghany H. Abdelghany
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
- Department of Anatomy, Faculty of Medicine, Alexandria University, Alexandria 21544, Egypt
| | - Shakir Idris
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
| | - Mai Alhadrami
- Department of Pathology, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia;
| | - Mohammad Althubiti
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; (R.A.A.); (M.Z.E.-R.); (M.A.); (M.E.E.); (S.Y.E.)
| | - Hussain A. Almasmoum
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
| | - Mazen M. Ghaith
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
| | - Mohamed E. Elzubeir
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; (R.A.A.); (M.Z.E.-R.); (M.A.); (M.E.E.); (S.Y.E.)
| | - Safaa Yehia Eid
- Department of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, Makkah 24381, Saudi Arabia; (R.A.A.); (M.Z.E.-R.); (M.A.); (M.E.E.); (S.Y.E.)
| | - Bassem Refaat
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, P.O. Box 7607, Makkah 24381, Saudi Arabia; (A.A.); (J.A.); (M.E.E.-B.); (A.H.A.); (S.I.); (H.A.A.); (M.M.G.)
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17
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Managò S, Tramontano C, Delle Cave D, Chianese G, Zito G, De Stefano L, Terracciano M, Lonardo E, De Luca AC, Rea I. SERS Quantification of Galunisertib Delivery in Colorectal Cancer Cells by Plasmonic-Assisted Diatomite Nanoparticles. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2021; 17:e2101711. [PMID: 34302422 DOI: 10.1002/smll.202101711] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/29/2021] [Indexed: 06/13/2023]
Abstract
The small molecule Galunisertib (LY2157299, LY) shows multiple anticancer activities blocking the transforming growth factor-β1 receptor, responsible for the epithelial-to-mesenchymal transition (EMT) by which colorectal cancer (CRC) cells acquire migratory and metastatic capacities. However, frequent dosing of LY can produce highly toxic metabolites. Alternative strategies to reduce drug side effects can rely on nanoscale drug delivery systems that have led to a medical revolution in the treatment of cancer, improving drug efficacy and lowering drug toxicity. Here, a hybrid nanosystem (DNP-AuNPs-LY@Gel) made of a porous diatomite nanoparticle decorated with plasmonic gold nanoparticles, in which LY is retained by a gelatin shell, is proposed. The multifunctional capability of the nanosystem is demonstrated by investigating the efficient LY delivery, the enhanced EMT reversion in CRCs and the intracellular quantification of drug release with a sub-femtogram resolution by surface-enhanced Raman spectroscopy (SERS). The LY release trigger is the pH sensitivity of the gelatin shell to the CRC acidic microenvironment. The drug release is real-time monitored at single-cell level by analyzing the SERS signals of LY in CRC cells. The higher efficiency of LY delivered by the DNP-AuNPs-LY@Gel complex paves the way to an alternative strategy for lowering drug dosing and consequent side effects.
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Affiliation(s)
- Stefano Managò
- National Research Council, Institute of Biochemistry and Cell Biology, Naples, 80131, Italy
| | - Chiara Tramontano
- National Research Council, Institute of Applied Sciences and Intelligent Systems, Unit of Naples, Naples, 80131, Italy
- University of Naples Federico II, Department of Pharmacy, Naples, 80131, Italy
| | - Donatella Delle Cave
- National Research Council, Institute of Genetics and Biophysics, Naples, 80131, Italy
| | - Giovanna Chianese
- National Research Council, Institute of Applied Sciences and Intelligent Systems, Unit of Naples, Naples, 80131, Italy
| | - Gianluigi Zito
- National Research Council, Institute of Applied Sciences and Intelligent Systems, Unit of Naples, Naples, 80131, Italy
| | - Luca De Stefano
- National Research Council, Institute of Applied Sciences and Intelligent Systems, Unit of Naples, Naples, 80131, Italy
| | - Monica Terracciano
- University of Naples Federico II, Department of Pharmacy, Naples, 80131, Italy
| | - Enza Lonardo
- National Research Council, Institute of Genetics and Biophysics, Naples, 80131, Italy
| | - Anna Chiara De Luca
- National Research Council, Institute of Biochemistry and Cell Biology, Naples, 80131, Italy
| | - Ilaria Rea
- National Research Council, Institute of Applied Sciences and Intelligent Systems, Unit of Naples, Naples, 80131, Italy
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Spontaneous Cell Detachment and Reattachment in Cancer Cell Lines: An In Vitro Model of Metastasis and Malignancy. Int J Mol Sci 2021; 22:ijms22094929. [PMID: 34066490 PMCID: PMC8124513 DOI: 10.3390/ijms22094929] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/27/2021] [Accepted: 04/30/2021] [Indexed: 11/16/2022] Open
Abstract
There is an unmet need for simplified in vitro models of malignancy and metastasis that facilitate fast, affordable and scalable gene and compound analysis. "Adherent" cancer cell lines frequently release "free-floating" cells into suspension that are viable and can reattach. This, in a simplistic way, mimics the metastatic process. We compared the gene expression profiles of naturally co-existing populations of floating and adherent cells in SW620 (colon), C33a (cervix) and HeLa (cervix) cancer cells. We found that 1227, 1367 and 1333 genes were at least 2-fold differentially expressed in the respective cell lines, of which 122 were shared among the three cell lines. As proof of principle, we focused on the anti-metastatic gene NM23-H1, which was downregulated both at the RNA and protein level in the floating cell populations of all three cell lines. Knockdown of NM23-H1 significantly increased the number of floating (and viable) cells, whereas overexpression of NM23-H1 significantly reduced the proportion of floating cells. Other potential regulators of these cellular states were identified through pathway analysis, including hypoxia, mTOR (mechanistic target of rapamycin), cell adhesion and cell polarity signal transduction pathways. Hypoxia, a condition linked to malignancy and metastasis, reduced NM23-H1 expression and significantly increased the number of free-floating cells. Inhibition of mTOR or Rho-associated protein kinase (ROCK) significantly increased cell death specifically in the floating and not the adherent cell population. In conclusion, our study suggests that dynamic subpopulations of free-floating and adherent cells is a useful model to screen and identify genes, drugs and pathways that regulate the process of cancer metastasis, such as cell detachment and anoikis.
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Abstract
In the field of molecular imaging, selectivity for target cells is a key determinant of the degree of imaging contrast. Previously, we developed a pre-targeted method by which target cells could be selectively imaged using a labeled N-glycan that was ligated in situ with an integrin-targeted cyclic RGD peptide on the cell surface. Here we demonstrate the power of our method in discriminating various cancerous and non-cancerous cells that cannot be distinguished using conventional RGD ligands. Using four cyclic RGDyK peptides with various linker lengths with five N-glycans, we identify optimal combinations to discriminate six types of αvβ3 integrin-expressing cells on 96-well plates. The optimal combinations of RGD and N-glycan ligands for the target cells are fingerprinted on the plates, and then used to selectively image tumors in xenografted mouse models. Using this method, various N-glycan molecules, even those with millimolar affinities for their cognate lectins, could be used for selective cancer cell differentiation.
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Chen J, Lou Q, He L, Wen C, Lin M, Zhu Z, Wang F, Huang L, Lan W, Iwamoto A, Yang X, Liu H. Reduced-gliotoxin induces ROS-mediated anoikis in human colorectal cancer cells. Int J Oncol 2018; 52:1023-1032. [PMID: 29393399 DOI: 10.3892/ijo.2018.4264] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 01/30/2018] [Indexed: 11/06/2022] Open
Abstract
Reduced-gliotoxin is a small molecule derived from the secondary metabolites of marine fungi; compared to other gliotoxin analogues, it exhibits potent anticancer effects. However, the molecular basis of the death of colorectal cancer (CRC) cells induced by reduced-gliotoxin is unclear. Thus, the aim of this study was to investigate the potency of reduced-gliotoxin against CRC cells and to elucidate the underlying mechanisms. Cell morphology, flow cytometric analysis and western bolt analysis were performed to examine the functions and mechanisms of cell death induced by reduced-gliotoxin. Our findings demonstrated that reduced-gliotoxin triggered rapid cell detachment and induced anoikis in CRC cells. Mechanistically, our data indicated that the anoikis induced by reduced-gliotoxin was associated with the disruption of integrin-associated cell detachment and multiple signaling pathways. Furthermore, reduced-gliotoxin induced the excessive production of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP), resulting in the activation of both endogenous and exogenous apoptotic pathways and eventually, in the apoptosis of CRC cells. The blockage of ROS generation with N-acetylcysteine (NAC) attenuated the anoikis induced by reduced-gliotoxin. Taken together, these results suggest that reduced-gliotoxin may prove to be a potential candidate in the treatment of CRC.
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Affiliation(s)
- Junxiong Chen
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Qiong Lou
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Lu He
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Chuangyu Wen
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Mengmeng Lin
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Zefeng Zhu
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Fang Wang
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Lanlan Huang
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Wenjian Lan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China
| | - Aikichi Iwamoto
- Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Xiangling Yang
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
| | - Huanliang Liu
- Guangdong Institute of Gastroenterology and the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, P.R. China
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Singh AK, Chauhan SS, Singh SK, Verma VV, Singh A, Arya RK, Maheshwari S, Akhtar MS, Sarkar J, Rangnekar VM, Chauhan PMS, Datta D. Dual targeting of MDM2 with a novel small-molecule inhibitor overcomes TRAIL resistance in cancer. Carcinogenesis 2017; 37:1027-1040. [PMID: 27543608 DOI: 10.1093/carcin/bgw088] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/16/2016] [Indexed: 01/25/2023] Open
Abstract
Mouse double minute 2 (MDM2) protein functionally inactivates the tumor suppressor p53 in human cancer. Conventional MDM2 inhibitors provide limited clinical application as they interfere only with the MDM2-p53 interaction to release p53 from MDM2 sequestration but do not prevent activated p53 from transcriptionally inducing MDM2 expression. Here, we report a rationally synthesized chalcone-based pyrido[ b ]indole, CPI-7c, as a unique small-molecule inhibitor of MDM2, which not only inhibited MDM2-p53 interaction but also promoted MDM2 degradation. CPI-7c bound to both RING and N-terminal domains of MDM2 to promote its ubiquitin-mediated degradation and p53 stabilization. CPI-7c-induced p53 directly recruited to the promoters of DR4 and DR5 genes and enhanced their expression, resulting in sensitization of TNF-related apoptosis-inducing ligand (TRAIL)-resistant cancer cells toward TRAIL-induced apoptosis. Collectively, we identified CPI-7c as a novel small-molecule inhibitor of MDM2 with a unique two-prong mechanism of action that sensitized TRAIL-resistant cancer cells to apoptosis by modulating the MDM2-p53-DR4/DR5 pathway.
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Affiliation(s)
| | - Shikha S Chauhan
- Medicinal and Process Chemistry Division and.,Present address: Pennsylvania State University, University Park, PA 16801, USA
| | - Sudhir Kumar Singh
- Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow, Uttar Pradesh 226031 , India
| | - Ved Vrat Verma
- Department of Biophysics, Delhi University , South Campus, New Delhi 110021 , India
| | | | | | - Shrankhla Maheshwari
- Biochemistry Division.,Academy of Scientific and Innovative Research, New Delhi 110025, India and
| | - Md Sohail Akhtar
- Molecular and Structural Biology Division, CSIR-Central Drug Research Institute , Lucknow, Uttar Pradesh 226031 , India
| | | | - Vivek M Rangnekar
- Department of Radiation Medicine and Markey Cancer Center, University of Kentucky , Lexington, KY 40536 , USA and
| | | | - Dipak Datta
- Biochemistry Division.,Academy of Scientific and Innovative Research, New Delhi 110025, India and
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22
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Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2017. [PMID: 27570424 DOI: 10.3748/wjg.vss.i30.6876] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
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Affiliation(s)
- Tao Hu
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Zhen Li
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Chun-Ying Gao
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
| | - Chi Hin Cho
- Tao Hu, Chi Hin Cho, School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong, China
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23
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Inhibition of Cdk5 induces cell death of tumor-initiating cells. Br J Cancer 2017; 116:912-922. [PMID: 28222068 PMCID: PMC5379151 DOI: 10.1038/bjc.2017.39] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 01/23/2017] [Accepted: 01/26/2017] [Indexed: 12/20/2022] Open
Abstract
Background: Tumour-initiating cells (TICs) account for chemoresistance, tumour recurrence and metastasis, and therefore represent a major problem in tumour therapy. However, strategies to address TICs are limited. Recent studies indicate Cdk5 as a promising target for anti-cancer therapy and Cdk5 has recently been associated with epithelial–mesenchymal transition (EMT). However, a role of Cdk5 in TICs has not been described yet. Methods: Expression of Cdk5 in human cancer tissue was analysed by staining of a human tissue microarray (TMA). Functional effects of Cdk5 overexpression, genetic knockdown by siRNA and shRNA, and pharmacologic inhibition by the small molecule roscovitine were tested in migration, invasion, cell death, and tumorsphere assays and in tumour establishment in vivo. For mechanistic studies, molecular biology methods were applied. Results: In fact, here we pin down a novel function of Cdk5 in TICs: knockdown and pharmacological inhibition of Cdk5 impaired tumorsphere formation and reduced tumour establishment in vivo. Conversely, Cdk5 overexpression promoted tumorsphere formation which was in line with increased expression of Cdk5 in human breast cancer tissues as shown by staining of a human TMA. In order to understand how Cdk5 inhibition affects tumorsphere formation, we identify a role of Cdk5 in detachment-induced cell death: Cdk5 inhibition induced apoptosis in tumorspheres by stabilizing the transcription factor Foxo1 which results in increased levels of the pro-apoptotic protein Bim. Conclusions: In summary, our study elucidates a Cdk5-Foxo1-Bim pathway in cell death in tumorspheres and suggests Cdk5 as a potential target to address TICs.
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Hu T, Li Z, Gao CY, Cho CH. Mechanisms of drug resistance in colon cancer and its therapeutic strategies. World J Gastroenterol 2016; 22:6876-6889. [PMID: 27570424 PMCID: PMC4974586 DOI: 10.3748/wjg.v22.i30.6876] [Citation(s) in RCA: 267] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/24/2016] [Accepted: 06/13/2016] [Indexed: 02/06/2023] Open
Abstract
Drug resistance develops in nearly all patients with colon cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. This review provides an up-to-date summary on over-expression of ATP-binding cassette (ABC) transporters and evasion of apoptosis, two representatives of transport-based and non-transport-based mechanisms of drug resistance, as well as their therapeutic strategies. Different ABC transporters were found to be up-regulated in colon cancer, which can facilitate the efflux of anticancer drugs out of cancer cells and decrease their therapeutic effects. Inhibition of ABC transporters by suppressing their protein expressions or co-administration of modulators has been proven as an effective approach to sensitize drug-resistant cancer cells to anticancer drugs in vitro. On the other hand, evasion of apoptosis observed in drug-resistant cancers also results in drug resistance to anticancer agents, especially to apoptosis inducers. Restoration of apoptotic signals by BH3 mimetics or epidermal growth factor receptor inhibitors and inhibition of cancer cell growth by alternative cell death pathways, such as autophagy, are effective means to treat such resistant cancer types. Given that the drug resistance mechanisms are different among colon cancer patients and may change even in a single patient at different stages, personalized and specific combination therapy is proposed to be more effective and safer for the reversal of drug resistance in clinics.
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25
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Ke B, Tian M, Li J, Liu B, He G. Targeting Programmed Cell Death Using Small-Molecule Compounds to Improve Potential Cancer Therapy. Med Res Rev 2016; 36:983-1035. [PMID: 27357603 DOI: 10.1002/med.21398] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 05/04/2016] [Accepted: 05/28/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Bowen Ke
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Mao Tian
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Jingjing Li
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Bo Liu
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
| | - Gu He
- Department of Anesthesiology, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy; West China Hospital, Sichuan University; Chengdu 610041 China
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26
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Lazarova DL, Bordonaro M. Vimentin, colon cancer progression and resistance to butyrate and other HDACis. J Cell Mol Med 2016; 20:989-93. [PMID: 27072512 PMCID: PMC4882977 DOI: 10.1111/jcmm.12850] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 02/25/2016] [Indexed: 12/17/2022] Open
Abstract
Dietary fibre protects against colorectal cancer (CRC) most likely through the activity of its fermentation product, butyrate. Butyrate functions as a histone deacetylase inhibitor (HDACi) that hyperactivates Wnt signalling and induces apoptosis of CRC cells. However, individuals who consume a high‐fibre diet may still develop CRC; therefore, butyrate resistance may develop over time. Furthermore, CRC cells that are resistant to butyrate are cross‐resistant to clinically relevant therapeutic HDACis, suggesting that the development of butyrate resistance in vivo can result in HDACi‐resistant CRCs. Butyrate/HDACi‐resistant CRC cells differ from their butyrate/HDACi‐sensitive counterparts in the expression of many genes, including the gene encoding vimentin (VIM) that is usually expressed in normal mesenchymal cells and is involved in cancer metastasis. Interestingly, vimentin is overexpressed in butyrate/HDACi‐resistant CRC cells although Wnt signalling is suppressed in such cells and that VIM is a Wnt activity‐targeted gene. The expression of vimentin in colonic neoplastic cells could be correlated with the stage of neoplastic progression. For example, comparative analyses of LT97 microadenoma cells and SW620 colon carcinoma cells revealed that although vimentin is not detectable in LT97 cells, it is highly expressed in SW620 cells. Based upon these observations, we propose that the differential expression of vimentin contributes to the phenotypic differences between butyrate‐resistant and butyrate‐sensitive CRC cells, as well as to the differences between early‐stage and metastatic colorectal neoplastic cells. We discuss the hypothesis that vimentin is a key factor integrating epithelial to mesenchymal transition, colonic neoplastic progression and resistance to HDACis.
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Affiliation(s)
- Darina L Lazarova
- Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA
| | - Michael Bordonaro
- Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA, USA
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27
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Li YH, Sun X, Wang HB. Role of CD24 in anoikis resistance of ovarian cancer cells. ACTA ACUST UNITED AC 2015; 35:390-396. [PMID: 26072079 DOI: 10.1007/s11596-015-1443-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 02/05/2015] [Indexed: 01/24/2023]
Abstract
This study examined the effect of CD24 on anoikis of ovarian cancer cells. The expression of CD24 was detected by RT-PCR and Western blotting in ovarian cancer cells with high metastatic potential (HO-8910PM cells) and low metastatic potential (A2780 cells). Cell viability and cell proliferation were detected by MTT assay in suspension culture and adhesion culture. Soft agar culture was used to observe the colony formation. Anoikis was flow cytometrically detected. The results showed that the expression levels of CD24 mRNA and protein were significantly higher in HO-8910PM cells than in A2780 cells (P<0.01). In the suspension culture and soft agar culture, the HO-8910PM cells formed larger and more colonies (35.33 ± 5.51 vs. 16.67 ± 4.04; P<0.01), and showed a stronger resistance to anoikis than A2780 cells did (cell apoptosis rate: 5.93% ± 2 .38% vs. 16.32% ± 2.00%; P<0.01). After treated with CD24 monoclonal antibodies, the number of colony formed in HO-8910PM and A2780 cells was significantly decreased (9.33 ± 2.52 and 8.00 ± 2.00, respectively), and the anoikis rate of the two cell lines was also markedly increased (23.11% ± 2.87% and 28.36% ± 2.29%, respectively). Our study suggested that CD24 may play an important role in the development of anoikis resistance and CD24 can be used as a new therapeutic target to induce anoikis and inhibit metastasis in ovarian cancer.
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Affiliation(s)
- Yan-Hui Li
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiang Sun
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Hong-Bo Wang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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28
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BRD4 inhibitor inhibits colorectal cancer growth and metastasis. Int J Mol Sci 2015; 16:1928-48. [PMID: 25603177 PMCID: PMC4307342 DOI: 10.3390/ijms16011928] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2014] [Accepted: 01/08/2015] [Indexed: 12/13/2022] Open
Abstract
Post-translational modifications have been identified to be of great importance in cancers and lysine acetylation, which can attract the multifunctional transcription factor BRD4, has been identified as a potential therapeutic target. In this paper, we identify that BRD4 has an important role in colorectal cancer; and that its inhibition substantially wipes out tumor cells. Treatment with inhibitor MS417 potently affects cancer cells, although such effects were not always outright necrosis or apoptosis. We report that BRD4 inhibition also limits distal metastasis by regulating several key proteins in the progression of epithelial-to-mesenchymal transition (EMT). This effect of BRD4 inhibitor is demonstrated via liver metastasis in animal model as well as migration and invasion experiments in vitro. Together, our results demonstrate a new application of BRD4 inhibitor that may be of clinical use by virtue of its ability to limit metastasis while also being tumorcidal.
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29
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Pro-apoptotic Bim suppresses breast tumor cell metastasis and is a target gene of SNAI2. Oncogene 2014; 34:3926-34. [PMID: 25263453 DOI: 10.1038/onc.2014.313] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 08/09/2014] [Accepted: 08/17/2014] [Indexed: 12/21/2022]
Abstract
Evasion of cell death is fundamental to the development of cancer and its metastasis. The role of the BCL-2-mediated (intrinsic) apoptotic program in these processes remains poorly understood. Here we have investigated the relevance of the pro-apoptotic protein BIM to breast cancer progression using the MMTV-Polyoma middle-T (PyMT) transgenic model. BIM deficiency in PyMT females did not affect primary tumor growth, but substantially increased the survival of metastatic cells within the lung. These data reveal a role for BIM in the suppression of breast cancer metastasis. Intriguingly, we observed a striking correlation between the expression of BIM and the epithelial to mesenchymal transition transcription factor SNAI2 at the proliferative edge of the tumors. Overexpression and knockdown studies confirmed that these two genes were coordinately expressed, and chromatin immunoprecipitation analysis further revealed that Bim is a target of SNAI2. Taken together, our findings suggest that SNAI2-driven BIM-induced apoptosis may temper metastasis by governing the survival of disseminating breast tumor cells.
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30
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Myers JN, Schäffer MW, Korolkova OY, Williams AD, Gangula PR, M’Koma AE. Implications of the colonic deposition of free hemoglobin-α chain: a previously unknown tissue by-product in inflammatory bowel disease. Inflamm Bowel Dis 2014; 20:1530-1547. [PMID: 25078150 PMCID: PMC4134710 DOI: 10.1097/mib.0000000000000144] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND We analyzed inflamed mucosal/submucosal layers of ulcerative colitis (UC = 63) and Crohn's colitis (CC = 50), and unexpectedly, we unveiled a pool of free hemoglobin alpha (Hb-α) chain. Patients with colitides have increased reactive oxidative stress (ROS), DNA oxidation products, free iron in mucosa, in preneoplastic, and in colitis-cancers and increased risks of developing colorectal cancer. All inflammatory bowel disease-related colorectal cancer lesions are found in segments with colitis. Linking this information, we investigated whether free Hb-α is key transformational stepping that increases colitis-related colorectal cancer vulnerability. METHODS UC/CC samples were profiled using matrix-assisted laser desorption/ionization mass spectrometry; protein identification was made by liquid chromatography. Diverticulitis was used as control (Ctrl). The presence of Hb(n) (n = α, β, or hemin)/Hb was validated by Western blotting and immunohistochemistry. We tested for DNA damage (DNAD) by exposing normal colonic epithelial cell line, NCM460, to 10 μM and 100 μM of Hb(n)/Hb, individually for 2, 6, and 12 hours. Quantification of Hb-α staining was done by Nikon Elements Advance Research Analysis software. ROS was measured by the production of 8-OHdG. DNAD was assessed by Comet assay. Colonic tissue homogenate antioxidants Nrf2-, CAT-, SOD-, and GPx-expressions were analyzed densitometrically/normalized by β-actin. RESULTS Immunohistochemistry of CC/UC mucosal/submucosal compartments stained strongly positive for Hb-α and significantly higher versus Ctrl. NCM460 exposed to Hb(n)/Hb exhibited steadily increasing ROS and subsequent DNAD. DNAD was higher in 10 μM than 100 μM in Hb-β/hemin the first 2 hours then plateaued followed by DNAD repair. This may be likely due to apoptosis in the later concentration. Nrf2 enzyme activities among UC, CC, and ulcerative colitis-associated colon cancer (UCAC) were observed impaired in all inflammatory bowel disease subjects. Decreased levels of Nrf2 among patients with UC versus patients with CC with active disease were insignificant as well as versus Ctrls but significantly lower in UCAC versus Ctrl. SOD was decreased in UC and UCAC and GPx in CC but statistically not significant. Comparing CC versus UC, SOD was significantly lower in CC (P < 0.05). CAT was observed increased among patients with CC/UC/UCAC and GPx in UC and UCAC versus Ctrl, respectively, and significantly increased in CC versus Ctrl (P < 0.01). CONCLUSIONS In the colitides, mucosal/submucosal tissue microenvironments demonstrated pool of free Hb-α chain. In vitro exposure of NCM460 cells to Hb(n)/Hb induced ROS and DNAD. Toxic effect of free Hb-α, in colonic epithelial cells, is therefore through production of ROS formation modulated by impairment of antioxidant effects. Targeting reduction-oxidation-sensitive pathways and transcription factors may offer options for inflammatory bowel disease-management and colitis-related cancer prevention.
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Affiliation(s)
- Jeremy N. Myers
- Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Michael W. Schäffer
- Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Olga Y. Korolkova
- Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Amanda D. Williams
- Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Pandu R. Gangula
- Department of Physiology, Meharry Medical College School of Medicine, Nashville, Tennessee
| | - Amosy E. M’Koma
- Department of Biochemistry and Cancer Biology, Meharry Medical College School of Medicine, Nashville, Tennessee
- Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee
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