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MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway.

ABSTRACT: Despite favorable responses to initial therapy, small-cell lung cancer (SCLC) relapse occurs within a year and exhibits resistance to multiple drugs. Because of limited accessibility of patient tissues for research purposes, SCLC patient-derived xenografts (PDX) have provided the best opportunity to address this limitation. Here, we sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface receptor in chemoresistant SCLC cell lines and in chemoresistant PDX compared with matched treatment-naïve tumors. MCAM depletion in chemoresistant cells reduced cell proliferation and reduced the IC50 inhibitory concentration of chemotherapeutic drugs in vitro This MCAM-mediated sensitization to chemotherapy occurred via SOX2-dependent upregulation of mitochondrial 37S ribosomal protein 1/ATP-binding cassette subfamily C member 1 (MRP1/ABCC1) and the PI3/AKT pathway. Metabolomic profiling revealed that MCAM modulated lactate production in chemoresistant cells that exhibit a distinct metabolic phenotype characterized by low oxidative phosphorylation. Our results suggest that MCAM may serve as a novel therapeutic target to overcome chemoresistance in SCLC. Cancer Res; 77(16); 4414-25. ©2017 AACR.

SUBMITTER: Tripathi SC

PROVIDER: S-EPMC5880621 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway.

Tripathi Satyendra C SC Fahrmann Johannes F JF Celiktas Muge M Aguilar Mitzi M Marini Kieren D KD Jolly Mohit K MK Katayama Hiroyuki H Wang Hong H Murage Eunice N EN Dennison Jennifer B JB Watkins D Neil DN Levine Herbert H Ostrin Edwin J EJ Taguchi Ayumu A Hanash Samir M SM

Cancer research 20170623 16

Despite favorable responses to initial therapy, small-cell lung cancer (SCLC) relapse occurs within a year and exhibits resistance to multiple drugs. Because of limited accessibility of patient tissues for research purposes, SCLC patient-derived xenografts (PDX) have provided the best opportunity to address this limitation. Here, we sought to identify novel mechanisms involved in SCLC chemoresistance. Through in-depth proteomic profiling, we identified MCAM as a markedly upregulated surface rece ...[more]

PMID: 28646020

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Project description:Background: Our previous studies have demonstrated that human papillomaviruse (HPV)-16 oncoproteins promoted epithelial-mesenchymal transition (EMT), leading to non-small cell lung cancer (NSCLC) progression, but the underlying molecular mechanisms still remain unclear. PI3K/Akt/HIF-1? signaling pathway has been reported to mediate hypoxia-induced EMT. In this study, we further explored the role of PI3K/Akt/HIF-1? signaling pathway in HPV-16 oncoprotein-induced EMT in NSCLC cells. Methods: A549 and NCI-H460 NSCLC cells were transiently transfected with pEGFP-HPV-16 E6 or E7 constructs. Western blotting and RT-qPCR were respectively performed to determine the protein and mRNA expression of EMT-related transcription factors. HPV-16 E6 or E7-transfected NSCLC cells were co-transfected with specific HIF-1?-siRNA or pretreated with different concentrations of LY294002, a specific PI3K inhibitor, followed by the analysis of expression of EMT-related transcription factors. The correlation between HIF-1? and EMT-related transcription factors in NSCLC tissues was analyzed by immunohistochemical staining and Spearman rank correlation coefficient. Results: HPV-16 E6 and E7 oncoproteins upregulated the expression of Slug and Twist1, the EMT-related transcription factors, at both protein and mRNA levels in A549 and NCI-H460 cells. The co-transfection with specific HIF-1?-siRNA, but not the non-specific (NS)-siRNA, significantly abrogated HPV-16 oncoprotein-induced upregulation of ZEB1, Snail1, Slug, and Twist1 at both protein and mRNA levels. Additionally, pretreatment with LY294002 obviously blocked HPV-16 E6- and E7-induced Snail1, Slug, and Twist1 protein expression in A549 and NCI-H460 cells. Further analysis of clinical specimens showed that HIF-1? protein was strongly expressed in NSCLC tissues, which was positively correlated with ZEB1, Snail1, Slug, and Twist1 protein expression. Conclusions: PI3K/Akt/HIF-1? may contribute to the progression of HPV-associated NSCLC via mediating the expression of EMT-related transcription factors in NSCLC cells.

Dataset Information

MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway.

Publications

MCAM Mediates Chemoresistance in Small-Cell Lung Cancer via the PI3K/AKT/SOX2 Signaling Pathway.

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