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CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3β axis
Pallavi Mohapatra, … , Ranjan K. Nanda, Rupesh Dash
Pallavi Mohapatra, … , Ranjan K. Nanda, Rupesh Dash
Published January 12, 2021
Citation Information: JCI Insight. 2021;6(4):e143643. https://doi.org/10.1172/jci.insight.143643.
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Research Article Cell biology Oncology

CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3β axis

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Abstract

Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT–glycogen synthase kinase-3β. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.

Authors

Pallavi Mohapatra, Omprakash Shriwas, Sibasish Mohanty, Arup Ghosh, Shuchi Smita, Sandeep Rai Kaushik, Rakesh Arya, Rachna Rath, Saroj Kumar Das Majumdar, Dillip Kumar Muduly, Sunil K. Raghav, Ranjan K. Nanda, Rupesh Dash

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Figure 2

CMTM6 is upregulated in chemoresistant squamous cell carcinomas.

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CMTM6 is upregulated in chemoresistant squamous cell carcinomas.
(A) Cel...
(A) Cell lysates from indicated resistant and sensitive OSCC cells were isolated and subjected to immunoblotting (n = 3) against CMTM6 and β-actin antibodies. (B) Relative mRNA (fold change) CMTM6 expression was analyzed by quantitative real-time PCR (qRT-PCR) in indicated cells (mean ± SEM, n = 3), *P < 0.05 by 1-way ANOVA. (C) Cell lysates from indicated resistant and sensitive OSCC cells were isolated and subjected to immunoblotting (n = 3) against CMTM6 and β-actin antibodies. (D) Relative mRNA (fold change) CMTM6 expression was analyzed by qRT-PCR in indicated cells (mean ± SEM, n = 3), *P < 0.05 by 1-way ANOVA. (E) Relative mRNA expression of CMTM6 was analyzed by qRT-PCR in different chemotherapy nonresponder (CT nonresponder) OSCC tumors as compared with CT responder tumors (median, n = 11 for CT responder and n = 23 for CT nonresponder). *P < 0.05 by 2-tailed Student’s t test. (F) Protein expression of CMTM6 was analyzed by IHC in CT responder and CT nonresponder OSCC tumors. Scale bars: 50 μm. (G) IHC scoring for CMTM6 from J (Q score = staining intensity × percent of staining) (median, n = 11 for CT responder and n = 23 for CT nonresponder). *P < 0.05 by 2-tailed Student’s t test. (H) CMTM6 protein expression was analyzed by IHC in pre– and post–TPF-treated paired tumor samples for CT nonresponder patients. Scale bars: 50 μm. (I) IHC scoring for CMTM6 from H (Q score = staining intensity × percent of IHC staining). (J) Relapse-free survival (RFS) plot for CMTM6 using Kaplain-Meier Plotter.
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