20.500.12556/RUL-137225 Dual effect of combined metformin and 2-deoxy-D-glucose treatment on mitochondrial biogenesis and PD-L1 expression in triple-negative breast cancer cells Metformin and 2-deoxy-D-glucose (2DG) exhibit multiple metabolic and immunomodulatory anti-cancer effects, such as suppressed proliferation or PD-L1 expression. Their combination or 2DG alone induce triple-negative breast cancer (TNBC) cell detachment, but their effects on mitochondria, crucial for anchorage-independent growth and metastasis formation, have not yet been evaluated. In the present study, we explored the effects of metformin, 2DG and their combination (metformin + 2DG) on TNBC cell mitochondria in vitro. Metformin + 2DG increased mitochondrial mass in TNBC cells. This was associated with an increased size but not number of morphologically normal mitochondria and driven by the induction of mitochondrial biogenesis rather than suppressed mitophagy. 2DG and metformin + 2DG strongly induced the unfolded protein response by inhibiting protein N-glycosylation. Together with adequate energy stress, this was one of the possible triggers of mitochondrial enlargement. Suppressed N-glycosylation by 2DG or metformin + 2DG also caused PD-L1 deglycosylation and reduced surface expression in MDA-MB-231 cells. PD-L1 was increased in low glucose and normalized by both drugs. 2DG and metformin + 2DG reduced PD-1 expression in Jurkat cells beyond the effects on activation, while cytokine secretion was mostly preserved. Despite increasing mitochondrial mass in TNBC cells, metformin and 2DG could therefore potentially be used as an adjunct therapy to improve anti-tumor immunity in TNBC. protein N-glycosylation ER stress AMPK PD-1/PD-L1 axis anchorage-independence metformin 2-deoxy-D-glucose triple-negative breast cancer T cells mitochondrial biogenesis triple negative breast neoplasms T-lymphocytes deoxyglucose organelle biogenesis true false true Angleški jezik Ni določen Članek v reviji 2022-06-07 14:37:44 2022-06-07 14:37:46 2022-09-15 04:14:48 0000-00-00 00:00:00 2022 0 0 30 str. iss. 5, art. 1343 Vol. 14 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 618.19-006 2072-6694 10.3390/cancers14051343 100035587 cancers-14-01343-v3.pdf cancers-14-01343-v3.pdf 1 D80029C8980060DF6663C4C337DC4A3F c634bef855d5053ed21e3057c19a27d53a03c306146bfef0d0c3d61f23590ae7 07331576-e65f-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=157104 https://www.mdpi.com/2072-6694/14/5/1343 1 7b75d821-e65e-11ec-8aca-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=157103 Medicinska fakulteta Fakulteta za elektrotehniko 0 0 0