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

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

doi:10.1172/jci.insight.143643

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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with approximately 53,260 new cases reported annually in the United States alone [1]
We identified 367 proteins to be differentially regulated in CisR4M and CisR8M as compared with cisplatin sensitive control cells (Supplemental Table 3)
Principal component analysis (PCA) using all identified proteins with their differential fold change values grouped them into 2 isolated clusters (Figure 1, A–C)

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with approximately 53,260 new cases reported annually in the United States alone [1]. Almost 90% of HNSCC cancer cases are oral squamous cell carcinoma (OSCC), which has emerged as the most common cancer in developing countries. In India, every year 80,000 new OSCC cases are reported with a mortality of approximately 46,000 [2]. The treatment modalities of advanced OSCC are surgical removal of primary tumor followed by chemotherapy (CT) and radiotherapy [3]. Neoadjuvant CT is commonly prescribed for surgically unresectable OSCC tumors [4]. Despite the availability of treatment modalities, the 5-year survival rate of patients with advanced tongue OSCC remains less than 50%, indicating therapy resistance

Methods

Results

Conclusion