Fig. 6
Schematic representation of the role of lipoic acid in sensitive or chemoresistant ovarian carcinoma cells. LA induces major apoptosis by up-regulation of Bim associated with down-regulation of Bcl-xL and Mcl-1. In explaining the Bim induction, the role of CHOP is highly suggested. CHOP induction would result from the over production of ROS induced by the reconnection of the TCA cycle and glycolysis induced by LA. In the metabolism of cancer cells, a disconnection between glycolysis and TCA cycle favours cancer cells growth. Lipoic acid reactivates PDH activity and thus, reconnects the glycolysis to the TCA cycle. This process leads to cell death presumably by generating oxidative stress characterized by ROS production. ROS promote ER stress; a process inducing CHOP expression. This expression upregulates the BH3 only pro-apoptotic factor Bim. On the other hand, LA is involved in the inhibition of Bcl-xL and Mcl-1, two major anti-apoptotic proteins, which conspire with bim to induce major apoptotic death. We suppose that the inhibition of Bcl-xL and Mcl-1 translates by the inactivation of PI3K/Akt/mTOR and ERK pathways, characterized by a decrease of various targets (such as PDK1, AKT, mTORC1, p70S6K…) leading to activation of GSK3. These assumptions which remain to be studied, are shown in blurred. Abbreviations: Acetyl-CoA: acetyl coenzyme a, α-KetoG: α -Ketoglutarate, OXPHOS: oxidative phosphorylation, ER: endoplasmic reticulum, Bim: Bcl-2 interacting mediator of cell death, PI3K: Phosphoinositide 3 kinase, PIP2: Phosphoinositide (3,4) biphosphate, PIP3: Phosphoinositide (3,4,5) triphosphate, mTORC1 or 2: mammalian target of rapamycin complex 1 or 2, Akt: protein kinase B, p70S6K: p70 S6 kinase, 4-EBP1: 4-E binding protein 1, GSK3: glycogen synthase kinase 3, NF-κB: nuclear factor-kappaB, Mcl-1: myeloid cell leukemia sequence 1, Ras: Rous Avian Sarcoma, MEK: MAPK/ERK kinase, ERK: extracellular signal-regulated MAP kinase