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

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 OSCC lines identified CMTM6 as top ranked up-regulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy-nonresponders as compared to chemotherapy-responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in ESCC, HNSCC was monitored from Kaplan-Meier-Plot analysis. Stable knockdown of CMTM6 restores cisplatinmediated cell death in chemoresistant OSCC lines. Similarly, upon CMTM6 overexpression in CMTM6KD lines, the cisplatin resistant phenotype was efficiently rescued. The patient-derived cell xenograft model of chemoresistant OSCC displayed CMTM6 depletion restored the cisplatin-induced cell death and tumor burden significantly. The transcriptome analysis of CMTM6KD and control chemoresistant cells depicted enrichment of Wnt-signaling pathway. Mechanistically, we demonstrated that CMTM6 interaction with membrane bound Enolase-1 stabilized its expression, leading to AKT-GSK3β mediated activation of Wnt-signaling. CMTM6 has been identified as a stabilizer of PD-L1 thereby facilitates immune evasion by tumor cells. As CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it can be an important therapeutic target for therapy resistant OSCC.

Wnt/β-Catenin Inhibition Disrupts Carboplatin Resistance in Isogenic Models of Triple-Negative Breast Cancer

“…In addition, several studies have demonstrated the involvement of this pathway in mediating resistance to chemotherapy and radiation in different types of cancer, including breast (30,34,(62)(63)(64). Wnt signaling is also known to specifically mediate platinum resistance in endometrial cancer (65), ovarian (66), and oral squamous cell carcinoma (67). However, little is known regarding the role of Wnt signaling in mediating resistance to platinum in TNBC.…”

Wnt/β-catenin inhibition disrupts drug-tolerance in isogenic carboplatin-resistant models of Triple-Negative Breast Cancer

“…We deemed this observation significant since Wnt signaling is intrinsically associated with tumorigenesis, and several studies have demonstrated the involvement of this pathway in mediating resistance to chemotherapy and radiation in different types of cancer, including breast (30,34,(58)(59)(60). Wnt signaling is also known to specifically mediate platinum resistance in endometrial cancer (61), ovarian (62), and oral squamous cell carcinoma (63). Nonetheless, little is known regarding the role of Wnt signaling in mediating resistance to platinum in TNBC.…”

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

“…Dysregulation of PI3K/Akt signaling prevails in human cancer and Akt often interacts with other signaling pathways involved in EMT/CSC to confer drug resistance. For instance, hypoxia synergistically enhanced gemcitabine-induced interaction between Akt and notch1, which in turn promoted cell stemness and chemoresistance [148] . Akt/glycogen synthase kinase 3-β activated Wnt signaling and promoted stemness and cisplatin resistance [149] .…”

“…For instance, hypoxia synergistically enhanced gemcitabine-induced interaction between Akt and notch1, which in turn promoted cell stemness and chemoresistance [ 148 ] . Akt/glycogen synthase kinase 3-β activated Wnt signaling and promoted stemness and cisplatin resistance [ 149 ] . Akt cross talks with MAPK and NF-κB inducing overexpression of P-gp and MDR in cancer cells with EMT/CSC phenotypes [ 128 , 150 ] , as well as activating programmed death-ligand 1 expression which leads to immunosuppression [ 147 ] .…”