STAT3 inhibitor enhances chemotherapy drug efficacy by modulating mucin 1 expression in non-small cell lung carcinoma

Abstract

Purpose: To evaluate the role of signal transducer and activator of transcription 3 (STAT3) and mucin 1(MUC1) in non-small cell lung carcinoma (NSCLC) and the use of their inhibitors to reduce chemoresistance.

Methods: Cisplatin or vinblastine was provided either with or without STAT3 inhibitor and evaluated for chemoresistance in NSCLC cells and a xenograft mice tumor model. Immunohistochemistry and Kaplan-Meier method of survival analysis were used to determine chemoresistance trends in patients. STAT3 inhibitor treatment, RNAi or ectopic overexpression of STAT3 or MUC1 in NSCLC cells were used to determine their inter-molecular relation and for modulating stemness-related genes.

Results: A major subset of chemoresistance patients exhibited a combined aberration of both STAT3 and MUC1 and exhibited a significantly reduced median overall survival (p = 0.008). Subsequent in vitro experiments in NSCLC cells showed that STAT3 levels modulate MUC1 expression (p < 0.01) and increase stemness gene expressions such as AKT (3-fold), OCT4 (4-fold), SOX2 (2-fold) and CXCR4 levels (2 -fold). In addition, co-treatment of STAT3 inhibitor with cisplatin or vinblastine enhanced drug efficiency in viability and invasion assays (p < 0.01) and in a xenograft mouse model (p < 0.05).

Conclusion: STAT3 inhibitor co-treatment with chemotherapy drugs increases drug efficacy and reduced tumor growth, and therefore, may improve outcomes in patients on NSCLC chemotherapies.

Keywords: STAT3, Non-small cell lung carcinoma, Mucin 1, Chemoresistance, Chemotherapy