S1, a novel BH3 mimetic, can induce apoptosis dependent on Bax/Bak through inhibition of Bcl-2 in various tumors. S1 also induces autophagy through interrupting the interaction of Bcl-2 and Beclin1. Our results showed that S1 induces apoptosis in human ovarian cancer SKOV3 cells in a time- and dose-dependent manner. Autophagy precedes apoptosis, in SKOV3 cells treated with S1 (6 mu mol/L), autophagy reached the maximum peak at 12 h after treatment and decreased to 24 h. In SKOV3 cells treated with different concentrations of S1 for 24 h, the highest level of autophagy was observed with 5 mu mol/L and decreased to 10 mu mol/L. Autophagy inhibitors 3-MA and CQ enhanced apoptosis induced by S1 in SKOV3 cells. However, overactivation of caspases in apoptosis induced by S1 may inhibit the autophagy-inducing function of Beclin1. Because the pan-caspase inhibitor Z-VAD recovered the autophagy-inducing function of Beclin1 through reduction of activated caspase-mediated cleavage of Beclin1. Furthermore, the Beclin1 cleavage products could further increase apoptosis induced by S1 in SKOV3 cells. This indicates that apoptosis induced by high doses and long exposure of S1 causes the overactivation of caspases and subsequent cleavage of Beclin1, and inhibits the protection of autophagy. Moreover, the cleaved product of Beclin1 further promotes apoptosis induced by S1 in SKOV3 cells. Our results suggest this may be a molecular mechanism for enhancing the sensitivity of cancer cells to apoptosis induced by small molecular compound targeting Bcl-2.
[1]Jilin Univ, Basic Med Coll, Dept Pathophysiol, Changchun 130021, Peoples R China.
[2]Jilin Univ, Hosp 1, Dept Obstet & Gynecol, Changchun 130021, Peoples R China.
[3]Jilin Med Coll, Med Res Lab, Jilin 132013, Peoples R China.
[4]Jilin Univ, Basic Med Coll, Dept Pathogen Microorganisms, Changchun 130021, Peoples R China.
[5]Dalian Univ Technol, State Key Lab Fine Chem, Sch Chem, Dalian 116012, Liaoning, Peoples R China.
(8.0+极速模式)