Investigating the potential therapeutic role of targeting STAT۳ for overcoming drug resistance by regulating energy metabolism in chronic myeloid leukemia cells

Objective(s): STATs are one of the initial targets of emerging anti-cancer agents due to their regulatory roles in survival, apoptosis, drug response, and cellular metabolism in CML. Aberrant STAT۳ activity promotes malignancy, and acts as a metabolic switcher in cancer cell metabolism, contributing to resistance to TKI nilotinib. To investigate the possible therapeutic effects of targeting STAT۳ to overcome nilotinib resistance by evaluating various cellular responses in both sensitive and nilotinib resistant CML cells and to test the hypothesis that energy metabolism modulation could be a mechanism for re-sensitization to nilotinib in resistant cells.Materials and Methods: By using RNAi-mediated STAT۳ gene silencing, cell viability and proliferation assays, apoptotic analysis, expressional regulations of STAT mRNA transcripts, STAT۳ total, pTyr۷۰۵, pSer۷۲۷ protein expression levels, and metabolic activity as energy metabolism was determined in CML model K۵۶۲ cells, in vitro.Results: Targeting STAT۳ sensitized both parental and especially nilotinib resistant cells by decreasing leukemic cell survival; inducing leukemic cell apoptosis, and decreasing STAT۳ mRNA and protein expression levels. Besides, cell energy phenotype was modulated by switching energy metabolism from aerobic glycolysis to mitochondrial respiration in resistant cells. RNAi-mediated STAT۳ silencing accelerated the sensitization of leukemia cells to nilotinib treatment, and STAT۳-dependent energy metabolism regulation could be another underlying mechanism for regaining nilotinib response.Conclusion: Targeting STAT۳ is an efficient strategy for improving the development of novel CML therapeutics for regaining nilotinib response, and re-sensitization of resistant cells could be mediated by induced apoptosis and regulation in energy metabolism.

Keywords:

Chemotherapeutic resistance , CML , Energy metabolism , Nilotinib , RNAi-based therapeutics , STAT۳ , Tyrosine kinase inhibitor