Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling

BACKGROUND: Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. METHODS: The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEM(sen)) and GEM-resistant (GEM(res)) pancreatic cancer cells. RESULTS: We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEM(sen) and GEM(res) cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEM(res) cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEM(res) cells than that in GEM(sen) cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEM(res) tumors, Evr significantly decreased the volume of GEM(res) tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. CONCLUSIONS: Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-021-00300-8.