TRAF6 promotes chemoresistance to paclitaxel of triple negative breast cancer via regulating PKM2-mediated glycolysis

Abstract

AbstractAmple evidence reveals that glycolysis plays an important role in cancer progression; however, the underlying mechanism of its drug resistance is still worth being further explored. TRAF6, a E3 ubiquitin ligase, is well known to overexpress in various types of cancers, which predicts poor prognosis. In our study, we discovered that TRAF6 expressed more significantly in triple negative breast cancer (TNBC) than in other subtypes of breast cancers, promoting chemoresistance to paclitaxel; that the inhibited TRAF6 expression in the chemoresistant TNBC (TNBC-CR) cells enhanced the sensitivity by decreasing glucose uptake and lactate production; that TRAF6 regulated glycolysis and facilitated chemoresistance via binding directly to PKM2; and that overexpressing PKM2 in the TNBC-CR cells with TRAF6 knocked down regained significantly TRAF6-dependent drug resistance and glycolysis. Additionally, we verified that TRAF6 could facilitate PKM2-mediated glycolysis and chemoresistance in the animal models and clinical tumor tissues. Thus, we identified the novel function of TRAF6 to promote glycolysis and chemoresistance in TNBC by regulating PKM2, which could provide a potential therapeutic target for TNBC treatment.