Toxicarioside H induces drug-resistant mitophagy via promoting expression of sirtuin-3 in lung cancer cells

Abstract

Cardenolides may have anticancer effects and toxicarioside H (ToxH), which we isolated, may have similar activity but its underlying mechanism against tumors is not clear. Herein, we report that ToxH treatment inhibited cell proliferation and induced mitochondrion-dependent apoptosis and mitophagy in human A549 and H460 lung cancer cells. ToxH treatment increased the expression of Sirt3, and inhibited Sirt3 expression via RNA interference against Sirt3 (siSirt3) suppressed mitophagy in ToxH-treated lung cancer cells. Stronger inhibition of cell proliferation and induction of apoptosis occurred when ToxH-mediated mitophagy was blocked by siSirt3. In addition, ToxH treatment redistributed hexokinase II from the mitochondria to the cytosol in A549 and H460 lung cancer cells, and decreased interaction of hexokinase II with VDAC1 was accompanied by the increased interaction of VDAC1 with parkin. Moreover, the disruption of Sirt3 by siSirt3 decreased the association of VDAC1 with parkin. Thus, ToxH induces drug-resistant mitophagy by enhancing the expression of Sirt3, which leads to the dissociation of hexokinase II from VDAC1 and increased binding of VDAC1 with parkin. Adding ToxH to a mitophagy inhibitor may thus be an effective strategy for treating lung cancer.