Mitochondrial dysfunction and chromatin changes with autophagy-mediated survival in doxorubicin resistant cancer cell lines.

Abstract

Acquired chemoresistance against doxorubicin remains an obstacle in long-term treatment. The comprehensive molecular mechanism underlying the acquirement of doxorubicin resistance has not been reported. The objective of the present study is to understand the survival strategies and investigate alternate treatments for doxorubicin-resistant cervical and liver cancer cells. In this study, doxorubicin-resistant sublines were established by continuous incremental exposure of the drug to parental cervical and liver cancer cells. The transcriptome data in drug-resistant model revealed downregulated energy production pathways like glycolysis, oxidative phosphorylation, and mTOR signalling. This resulted in slow proliferation and altered mitochondrial changes in doxorubicin-resistant cells. The altered metabolic state of the resistant cells was associated with hypo-acetylation of chromatin. Pre-treatment with HDACi sensitized the drug-resistant cells to doxorubicin by increased drug accumulation in the cells, thereby leading to apoptosis. Additionally, we demonstrated that autophagy gets activated in doxorubicin-resistant cervical and liver cancer cells. Autophagy acts as pro-survival mechanism in resistant cells, as inhibition of autophagy leads to cell death. In conclusion, the data highlights survival ability of resistant cells with mitochondrial dysfunction, altered chromatin state, and pro-survival autophagy. The study proposes targeting chromatin alteration with the combinatorial treatment of HDACi with doxorubicin or survival mechanism through autophagy inhibitor against doxorubicin-resistant cancer phenotype.