Pentose phosphate pathway inhibition potentiates metformin cytotoxic effects on HNSCC cells

VILLAVERDE M. S.; GUTKIND, JS

Congreso; AACR Annual Meeting; 2020

AbstractThe pentose phosphate pathway (PPP) enables cancer cells to adapt to anabolic demands that require rapid DNA, RNA, and lipid synthesis and to oxidative cellular stress. Metformin can efficiently inhibit the malignant progression of oral premalignant lesions by indirectly inhibiting the mammalian target of rapamycin (mTORC1). Frequently activated in cancer cells, mTORC1 may upregulate the oxidative branch of the pentose phosphate pathway (PPP) through the sterol regulatory element binding protein (SREBP1). Our previous results showed that the combination of metformin and 6-AN (a PPP inhibitor) strongly potentiates their individual cytotoxic effects on melanoma, glioblastoma, mammary and colon carcinoma cell lines. However, the mechanism of this synergism remains unclear. In this context, the aim of this project was to determine the cell signaling events underlying the therapeutic potential of this combinatory approach, against HNSCC cell lines. Then, we study the effect of metformin alone or in combination with 6-AN on AMPK/mTOR/S6K/S6 and SREBP1 pathway. We found that the inhibition of PPP strongly potentiated metformin cytotoxic effect on 2D and 3D cultures of CAL33 and HN12, both HNSCC cell lines. Furthermore, the combination synergized to increase the activation of AMPK, concomitant with decreased phosphorylation of mTOR, decreased phosphorylation of S6K and decreased phosphorylation of S6. Interestingly, activation of SREBP1 was also synergistically decreased by this combinatory approach. We conclude that the inhibition of PPP and metformin converges to inhibit mTOR pathway. This interaction deserves to be further investigated as a potential strategy to potentiate metformin therapy.