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

JCI Insight. 2021 Feb 22;6(4):e143643. 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.

Keywords: Cell Biology; Head and neck cancer; Molecular biology; Oncology; Signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Death
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • DNA-Binding Proteins / metabolism*
  • Drug Resistance, Neoplasm / drug effects*
  • Esophageal Neoplasms / genetics
  • Esophageal Squamous Cell Carcinoma / drug therapy
  • Esophageal Squamous Cell Carcinoma / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Head and Neck Neoplasms / drug therapy
  • Head and Neck Neoplasms / genetics
  • Humans
  • MARVEL Domain-Containing Proteins
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mouth Neoplasms / drug therapy
  • Mouth Neoplasms / pathology
  • Myelin Proteins / genetics
  • Myelin Proteins / metabolism*
  • Phosphopyruvate Hydratase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation / drug effects
  • Wnt Signaling Pathway / drug effects*

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • CMTM6 protein, human
  • DNA-Binding Proteins
  • MARVEL Domain-Containing Proteins
  • Myelin Proteins
  • Tumor Suppressor Proteins
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • ENO1 protein, human
  • Phosphopyruvate Hydratase
  • Cisplatin