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1
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Targeting EGFR in melanoma - The sea of possibilities to overcome drug resistance. Biochim Biophys Acta Rev Cancer 2022; 1877:188754. [PMID: 35772580 DOI: 10.1016/j.bbcan.2022.188754] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/15/2022] [Accepted: 06/23/2022] [Indexed: 12/21/2022]
Abstract
Melanoma is considered one of the most aggressive skin cancers. It spreads and metastasizes quickly and is intrinsically resistant to most conventional chemotherapeutics, thereby presenting a challenge to researchers and clinicians searching for effective therapeutic strategies to treat patients with melanoma. The use of inhibitors of mutated serine/threonine-protein kinase B-RAF (BRAF), e.g., vemurafenib and dabrafenib, has revolutionized melanoma chemotherapy. Unfortunately, the response to these drugs lasts a limited time due to the development of acquired resistance. One of the proteins responsible for this process is epidermal growth factor receptor (EGFR). In this review, we summarize the role of EGFR signaling in the multidrug resistance of melanomas and discuss possible applications of EGFR inhibitors to overcome the development of drug resistance in melanoma cells during therapy.
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2
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Insights into the Mechanisms of Action of MDA-7/IL-24: A Ubiquitous Cancer-Suppressing Protein. Int J Mol Sci 2021; 23:ijms23010072. [PMID: 35008495 PMCID: PMC8744595 DOI: 10.3390/ijms23010072] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 11/23/2022] Open
Abstract
Melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24), a secreted protein of the IL-10 family, was first identified more than two decades ago as a novel gene differentially expressed in terminally differentiating human metastatic melanoma cells. MDA-7/IL-24 functions as a potent tumor suppressor exerting a diverse array of functions including the inhibition of tumor growth, invasion, angiogenesis, and metastasis, and induction of potent "bystander" antitumor activity and synergy with conventional cancer therapeutics. MDA-7/IL-24 induces cancer-specific cell death through apoptosis or toxic autophagy, which was initially established in vitro and in preclinical animal models in vivo and later in a Phase I clinical trial in patients with advanced cancers. This review summarizes the history and our current understanding of the molecular/biological mechanisms of MDA-7/IL-24 action rendering it a potent cancer suppressor.
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3
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Contribution of Apaf-1 to the pathogenesis of cancer and neurodegenerative diseases. Biochimie 2021; 190:91-110. [PMID: 34298080 DOI: 10.1016/j.biochi.2021.07.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 06/24/2021] [Accepted: 07/12/2021] [Indexed: 01/02/2023]
Abstract
Deregulation of apoptosis is associated with various pathologies, such as neurodegenerative disorders at one end of the spectrum and cancer at the other end. Generally speaking, differentiated cells like cardiomyocytes, skeletal myocytes and neurons exhibit low levels of Apaf-1 (Apoptotic protease activating factor 1) protein suggesting that down-regulation of Apaf-1 is an important event contributing to the resistance of these cells to apoptosis. Nonetheless, upregulation of Apaf-1 has not emerged as a common phenomenon in pathologies associated with enhanced neuronal cell death, i.e., neurodegenerative diseases. In cancer, on the other hand, Apaf-1 downregulation is a common phenomenon, which occurs through various mechanisms including mRNA hyper-methylation, gene methylation, Apaf-1 localization in lipid rafts, inhibition by microRNAs, phosphorylation, and interaction with specific inhibitors. Due to the diversity of these mechanisms and involvement of other factors, defining the exact contribution of Apaf-1 to the development of cancer in general and neurodegenerative disorders, in particular, is complicated. The current review is an attempt to provide a comprehensive image of Apaf-1's contribution to the pathologies observed in cancer and neurodegenerative diseases with the emphasis on the therapeutic aspects of Apaf-1 as an important target in these pathologies.
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4
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Sabbah M, Najem A, Krayem M, Awada A, Journe F, Ghanem GE. RTK Inhibitors in Melanoma: From Bench to Bedside. Cancers (Basel) 2021; 13:1685. [PMID: 33918490 PMCID: PMC8038208 DOI: 10.3390/cancers13071685] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023] Open
Abstract
MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.
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Affiliation(s)
- Malak Sabbah
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ahmad Najem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Mohammad Krayem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ahmad Awada
- Medical Oncolgy Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium;
| | - Fabrice Journe
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ghanem E. Ghanem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
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5
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Wu Z, Liu W, Wang Z, Zeng B, Peng G, Niu H, Chen L, Liu C, Hu Q, Zhang Y, Pan M, Wu L, Liu M, Liu X, Liang D. Mesenchymal stem cells derived from iPSCs expressing interleukin-24 inhibit the growth of melanoma in the tumor-bearing mouse model. Cancer Cell Int 2020; 20:33. [PMID: 32015693 PMCID: PMC6990536 DOI: 10.1186/s12935-020-1112-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 01/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background Interleukin-24 (IL-24) is a therapeutic gene for melanoma, which can induce melanoma cell apoptosis. Mesenchymal stem cells (MSCs) show promise as a carrier to delivery anti-cancer factors to tumor tissues. Induced pluripotent stem cells (iPSCs) are an alternative source of mesenchymal stem cells (MSCs). We previously developed a novel non-viral gene targeting vector to target IL-24 to human iPSCs. This study aims to investigate whether MSCs derived from the iPSCs with the site-specific integration of IL-24 can inhibit the growth of melanoma in a tumor-bearing mouse model via retro-orbital injection. Methods IL-24-iPSCs were differentiated into IL-24-iMSCs in vitro, of which cellular properties and potential of differentiation were characterized. The expression of IL-24 in the IL-24-iMSCs was measured by qRT-PCR, Western Blotting, and ELISA analysis. IL-24-iMSCs were transplanted into the melanoma-bearing mice by retro-orbital intravenous injection. The inhibitory effect of IL-24-iMSCs on the melanoma cells was investigated in a co-culture system and tumor-bearing mice. The molecular mechanisms underlying IL-24-iMSCs in exerting anti-tumor effect were also explored. Results iPSCs-derived iMSCs have the typical profile of cell surface markers of MSCs and have the ability to differentiate into osteoblasts, adipocytes, and chondroblasts. The expression level of IL-24 in IL-24-iMSCs reached 95.39 ng/106 cells/24 h, which is significantly higher than that in iMSCs, inducing melanoma cells apoptosis more effectively in vitro compared with iMSCs. IL-24-iMSCs exerted a significant inhibitory effect on the growth of melanoma in subcutaneous mouse models, in which the migration of IL-24-iMSCs to tumor tissue was confirmed. Additionally, increased expression of Bax and Cleaved caspase-3 and down-regulation of Bcl-2 were observed in the mice treated with IL-24-iMSCs. Conclusion MSCs derived from iPSCs with the integration of IL-24 at rDNA locus can inhibit the growth of melanoma in tumor-bearing mouse models when administrated via retro-orbital injection.
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Affiliation(s)
- Zheng Wu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Wei Liu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Zujia Wang
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Baitao Zeng
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Guangnan Peng
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Hongyan Niu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Linlin Chen
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Cong Liu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Qian Hu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Yuxuan Zhang
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Mengmeng Pan
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China
| | - Lingqian Wu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
| | - Mujun Liu
- 2Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
| | - Xionghao Liu
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
| | - Desheng Liang
- 1Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan China.,3Hunan Key Laboratory of Animal Model for Human Diseases, Central South University, Changsha, Hunan China
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Han R, Chen XY. Apoptotic protease activating factor-1 negatively regulates Wnt signaling in hepatocellular carcinoma. Kaohsiung J Med Sci 2019; 35:459-466. [PMID: 31094091 DOI: 10.1002/kjm2.12089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 04/30/2019] [Indexed: 11/07/2022] Open
Abstract
The current study aims to evaluate the mechanism of apoptotic protease activating factor-1 (Apaf-1) in hepatocellular carcinoma (HCC) cells by verifying the regulation of the wnt/beta-catenin signaling pathway via Apal-1. Our data showed that transfection with Ad-Apaf-1 could inhibit the activity of a lymphoid enhancer factor (LEF) luciferase plasmid activated by β-catenin. Overexpressing Apaf-1 could suppress the β-catenin-induced LEF luciferase activity in a dose-dependent manner. Western blot assays demonstrated that the overexpression of Apaf1 significantly suppressed the expression of Wnt/β-catenin signaling-related proteins. Further study demonstrated that Apaf-1 suppressed HepG2 cell migration, invasion, and viability. Knocking down the expression of Apaf-1 activated the wnt/β-catenin pathway in HepG2 cells. In contrast, silencing β-catenin decreased the activation of wnt/β-catenin, even in the presence of si-Apaf-1. Cell cycle distribution analysis demonstrated a decrease in the number of cells in the G0/G1 phase in the Apaf-1 silencing group. In contrast, knocking down the expression of β-catenin increased the number of cells in the G0/G1 phase, even in the presence of si-Apaf-1. In summary, the Apaf-1-mediated suppression of HepG2 cell malignancy is achieved by inhibiting the wnt/β-catenin pathway.
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Affiliation(s)
- Rui Han
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China.,Department of Epidemiology and Public Health, School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Xin-Yi Chen
- Department of Oncology and Hematology, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, P. R. China
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Abstract
Subtraction hybridization identified genes displaying differential expression as metastatic human melanoma cells terminally differentiated and lost tumorigenic properties by treatment with recombinant fibroblast interferon and mezerein. This approach permitted cloning of multiple genes displaying enhanced expression when melanoma cells terminally differentiated, called melanoma differentiation associated (mda) genes. One mda gene, mda-7, has risen to the top of the list based on its relevance to cancer and now inflammation and other pathological states, which based on presence of a secretory sequence, chromosomal location, and an IL-10 signature motif has been named interleukin-24 (MDA-7/IL-24). Discovered in the early 1990s, MDA-7/IL-24 has proven to be a potent, near ubiquitous cancer suppressor gene capable of inducing cancer cell death through apoptosis and toxic autophagy in cancer cells in vitro and in preclinical animal models in vivo. In addition, MDA-7/IL-24 embodied profound anticancer activity in a Phase I/II clinical trial following direct injection with an adenovirus (Ad.mda-7; INGN-241) in tumors in patients with advanced cancers. In multiple independent studies, MDA-7/IL-24 has been implicated in many pathological states involving inflammation and may play a role in inflammatory bowel disease, psoriasis, cardiovascular disease, rheumatoid arthritis, tuberculosis, and viral infection. This review provides an up-to-date review on the multifunctional gene mda-7/IL-24, which may hold potential for the therapy of not only cancer, but also other pathological states.
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Tormo E, Adam-Artigues A, Ballester S, Pineda B, Zazo S, González-Alonso P, Albanell J, Rovira A, Rojo F, Lluch A, Eroles P. The role of miR-26a and miR-30b in HER2+ breast cancer trastuzumab resistance and regulation of the CCNE2 gene. Sci Rep 2017; 7:41309. [PMID: 28120942 PMCID: PMC5264595 DOI: 10.1038/srep41309] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 12/19/2016] [Indexed: 01/05/2023] Open
Abstract
A subset of HER2+ breast cancer patients manifest clinical resistance to trastuzumab. Recently, miR-26a and miR-30b have been identified as trastuzumab response regulators, and their target gene CCNE2 seems to play an important role in resistance to trastuzumab therapy. Cell viability was evaluated in trastuzumab treated HER2+ BT474 wt (sensitive), BT474r (acquired resistance), HCC1954 (innate resistance), and MDA-MB-231 (HER2−) cell lines, and the expression of miR-26a, miR-30b, and their target genes was measured. BT474 wt cell viability decreased by 60% and miR-26a and miR-30b were significantly overexpressed (~3-fold, p = 0.003 and p = 0.002, respectively) after trastuzumab treatment, but no differences were observed in resistant and control cell lines. Overexpression of miR-30b sensitized BT474r cells to trastuzumab (p = 0.01) and CCNE2, was significantly overexpressed after trastuzumab treatment in BT474r cells (p = 0.032), but no significant changes were observed in sensitive cell line. When CCNE2 was silenced BT474r cell sensitivity to trastuzumab increased (p = 0.03). Thus, the molecular mechanism of trastuzumab action in BT474 cell line may be regulated by miR-26a and miR-30b and CCNE2 overexpression might play an important role in acquired trastuzumab resistance in HER2+ breast cancer given that resistance was diminished when CCNE2 was silenced.
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Affiliation(s)
- Eduardo Tormo
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
| | | | | | - Begoña Pineda
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
| | - Sandra Zazo
- Pathology Department, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain
| | | | - Joan Albanell
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain.,Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain.,Pompeu Fabra University, 08002 Barcelona, Spain
| | - Ana Rovira
- Cancer Research Program, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain.,Medical Oncology Department, Hospital del Mar, 08003 Barcelona, Spain
| | - Federico Rojo
- Pathology Department, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain
| | - Ana Lluch
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain.,Oncology and Hematology Department, Hospital Clínico Universitario, 46010 Valencia, Spain
| | - Pilar Eroles
- INCLIVA Biomedical Research Institute, 46010 Valencia, Spain
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9
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Du Y, Long Q, Shi Y, Liu X, Li X, Zeng J, Gong Y, Li L, Wang X, He D. Insulin-like growth factor binding protein-3 mediates interleukin-24-induced apoptosis through inhibition of the mTOR pathway in prostate cancer. Oncol Rep 2015; 34:2273-81. [PMID: 26323436 PMCID: PMC4583521 DOI: 10.3892/or.2015.4201] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Accepted: 07/07/2015] [Indexed: 12/11/2022] Open
Abstract
IGF-binding protein-3 (IGFBP-3) has been shown to induce apoptosis in an insulin-like growth factor (IGF)-independent manner in various cell systems, however, the underlying molecular mechanisms remain unknown. In the present study, we showed that IGFBP-3 significantly enhanced interleukin-24 (IL-24)-induced cell death in prostate cancer (PC) cell lines in vitro. Both the addition of IGFBP-3 to cell medium or the enforced expression of IGFBP-3 in the PC cell line inhibited activation of mammalian target of rapamycin (mTOR). Downregulation of mTOR/S6K reduced Mcl-1 protein expression and consequently promoted sensitization to IL-24 treatment. Overexpression of Mcl-1 reduced the level of cleaved poly(ADP-ribose) polymerase (PARP) induced by IL-24 and IGFBP-3, suggesting that the IL-24-induced apop-tosis is realized by way of Mcl-1. We then showed that the combination of IL-24 and IGFBP-3 significantly suppressed PC tumor growth in vivo. We propose that the IGFBP-3 and IL-24 non-toxic mTOR inhibitors can be used as an adjuvant in the treatment of PC.
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Affiliation(s)
- Yuefeng Du
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Qingzhi Long
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Ying Shi
- Department of Urology, Tongji Medical College Union Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Xiaogang Liu
- School of Life Science and Technology, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Xudong Li
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Jin Zeng
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Yongguang Gong
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Lei Li
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Xinyang Wang
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
| | - Dalin He
- Department of Urology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China
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Othman N, Nagoor NH. The role of microRNAs in the regulation of apoptosis in lung cancer and its application in cancer treatment. BIOMED RESEARCH INTERNATIONAL 2014; 2014:318030. [PMID: 24999473 PMCID: PMC4068038 DOI: 10.1155/2014/318030] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 05/20/2014] [Indexed: 02/07/2023]
Abstract
Lung cancer remains to be one of the most common and serious types of cancer worldwide. While treatment is available, the survival rate of this cancer is still critically low due to late stage diagnosis and high frequency of drug resistance, thus highlighting the pressing need for a greater understanding of the molecular mechanisms involved in lung carcinogenesis. Studies in the past years have evidenced that microRNAs (miRNAs) are critical players in the regulation of various biological functions, including apoptosis, which is a process frequently evaded in cancer progression. Recently, miRNAs were demonstrated to possess proapoptotic or antiapoptotic abilities through the targeting of oncogenes or tumor suppressor genes. This review examines the involvement of miRNAs in the apoptotic process of lung cancer and will also touch on the promising evidence supporting the role of miRNAs in regulating sensitivity to anticancer treatment.
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Affiliation(s)
- Norahayu Othman
- Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Noor Hasima Nagoor
- Division of Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603 Kuala Lumpur, Malaysia
- Centre for Research in Biotechnology for Agriculture (CEBAR), University of Malaya, 50603 Kuala Lumpur, Malaysia
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11
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Bombelli FB, Webster CA, Moncrieff M, Sherwood V. The scope of nanoparticle therapies for future metastatic melanoma treatment. Lancet Oncol 2014; 15:e22-32. [PMID: 24384491 DOI: 10.1016/s1470-2045(13)70333-4] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Metastatic melanoma is a highly aggressive malignancy that has traditionally been very difficult to treat. However, after decades of basic research into the signal transduction pathways that promote cancer cell survival, chemoresistance, growth, and crosstalk with the immune system, targeted therapies have now been developed that offer improved survival for patients with metastatic melanoma. Some of the most promising therapies that have been developed include ipilimumab, an anti-cytotoxic T lymphocyte antigen 4 antibody that enhances T-cell activity in the tumour, and selective BRAF inhibitors, such as vemurafenib that blocks tumour cell proliferation in patients with activating BRAF mutations. Although these treatments offer substantial hope for patients, they are not without their drawbacks, which include adverse side-effects, drug resistance, and eventual relapse. Nanotherapeutics holds significant promise to circumvent these shortcomings and has the additional advantage of potentially functioning as a diagnostic device. We will discuss the scope of the use of such multimodal nanoparticles for melanoma treatment and ask whether such particles can offer patients with metastatic melanoma improved prognoses for the future.
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Affiliation(s)
- Francesca Baldelli Bombelli
- School of Pharmacy, University of East Anglia, Norwich, Norfolk, UK; CEN-European Centre For Nanomedicine, C/O Dipartimento di Chimica, Materiali ed Ingegneria Chimica "Giulio Natta", Politecnico di Milano, Milan, Italy
| | - Carl A Webster
- School of Pharmacy, University of East Anglia, Norwich, Norfolk, UK
| | - Marc Moncrieff
- Norfolk and Norwich University Hospital, Norwich, Norfolk, UK
| | - Victoria Sherwood
- School of Pharmacy, University of East Anglia, Norwich, Norfolk, UK.
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12
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Whitaker EL, Filippov VA, Duerksen-Hughes PJ. Interleukin 24: Mechanisms and therapeutic potential of an anti-cancer gene. Cytokine Growth Factor Rev 2012; 23:323-31. [DOI: 10.1016/j.cytogfr.2012.08.004] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2012] [Accepted: 08/20/2012] [Indexed: 12/18/2022]
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13
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Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol 2012; 3:32-42. [PMID: 22442756 PMCID: PMC3309891 DOI: 10.5306/wjco.v3.i3.32] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/12/2012] [Accepted: 03/05/2012] [Indexed: 02/06/2023] Open
Abstract
Cutaneous malignant melanoma is the most aggressive form of skin cancer with an extremely poor survival rate for the patients diagnosed with locally invasive and metastatic disease states. Intensive research has led in last few years to an improvement of the early detection and curative treatment of primary cutaneous melanomas that are confined to the skin by tumor surgical resection. However, locally advanced and disseminated melanomas are generally resistant to conventional treatments, including ionizing radiation, systemic chemotherapy, immunotherapy and/or adjuvant stem cell-based therapies, and result in the death of patients. The rapid progression of primary melanomas to locally invasive and/or metastatic disease states remains a major obstacle for an early effective diagnosis and a curative therapeutic intervention for melanoma patients. Importantly, recent advances in the melanoma research have led to the identification of different gene products that are often implicated in the malignant transformation of melanocytic cells into melanoma cells, including melanoma stem/progenitor cells, during melanoma initiation and progression to locally advanced and metastatic disease states. The frequent deregulated genes products encompass the oncogenic B-RafV600E and N-RasQ61R mutants, different receptor tyrosine kinases and developmental pathways such as epidermal growth factor receptor (EGFR), stem cell-like factor (SCF) receptor KIT, hedgehog, Wnt/β-catenin, Notch, stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor-4 (CXCR4) and vascular endothelial growth factor (VEGF)/VEGFR receptor. These growth factors can cooperate to activate distinct tumorigenic downstream signaling elements and epithelial-mesenchymal transition (EMT)-associated molecules, including phosphatidylinositol 3’-kinase (PI3K)/Akt/ molecular target of rapamycin (mTOR), nuclear factor-kappaB (NF-κB), macrophage inhibitory cytokine-1 (MIC-1), vimentin, snail and twist. Of therapeutic relevance, these deregulated signal transduction components constitute new potential biomarkers and therapeutic targets of great clinical interest for improving the efficacy of current diagnostic and prognostic methods and management of patients diagnosed with locally advanced, metastatic and/or relapsed melanomas.
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Affiliation(s)
- Murielle Mimeault
- Murielle Mimeault, Surinder K Batra, Department of Biochemistry and Molecular Biology, College of Medicine, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5870, United States
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MDA-7/IL-24 Expression and Its Relation with Clinicopathologic Factors in Lung Adenocarcinomas of 3 cm or Less in Diameter. ACTA ACUST UNITED AC 2012. [DOI: 10.6058/jlc.2012.11.2.71] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Madhunapantula SV, Mosca PJ, Robertson GP. The Akt signaling pathway: an emerging therapeutic target in malignant melanoma. Cancer Biol Ther 2011; 12:1032-49. [PMID: 22157148 DOI: 10.4161/cbt.12.12.18442] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Studies using cultured melanoma cells and patient tumor biopsies have demonstrated deregulated PI3 kinase-Akt3 pathway activity in ~70% of melanomas. Furthermore, targeting Akt3 and downstream PRAS40 has been shown to inhibit melanoma tumor development in mice. Although these preclinical studies and several other reports using small interfering RNAs and pharmacological agents targeting key members of this pathway have been shown to retard melanoma development, analysis of early Phase I and Phase II clinical trials using pharmacological agents to target this pathway demonstrate the need for (1) selection of patients whose tumors have PI3 kinase-Akt pathway deregulation, (2) further optimization of therapeutic agents for increased potency and reduced toxicity, (3) the identification of additional targets in the same pathway or in other signaling cascades that synergistically inhibit the growth and progression of melanoma, and (4) better methods for targeted delivery of pharmaceutical agents inhibiting this pathway. In this review we discuss key potential targets in PI3K-Akt3 signaling, the status of pharmacological agents targeting these proteins, drugs under clinical development, and strategies to improve the efficacy of therapeutic agents targeting this pathway.
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Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A, Sun J, Lovat F, Alder H, Condorelli G, Engelman JA, Ono M, Rho JK, Cascione L, Volinia S, Nephew KP, Croce CM. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nat Med 2011; 18:74-82. [PMID: 22157681 PMCID: PMC3467100 DOI: 10.1038/nm.2577] [Citation(s) in RCA: 324] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 10/20/2011] [Indexed: 12/13/2022]
Abstract
The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.
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Affiliation(s)
- Michela Garofalo
- Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA
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