Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway

Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon exhibited broad-spectrum antitumor activity via different molecular mechanisms. In the present study, we investigated the effect of shikonin on the mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasion of HCCLM3 cells, and meanwhile, promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanism underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK an...