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Caspase-mediated cleavage of Beclin1 inhibits autophagy and promotes apoptosis induced by S1 in human ovarian cancer SKOV3 cells

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Abstract

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 μmol/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 μmol/L and decreased to 10 μmol/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.

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Abbreviations

Bcl:

B cell lymphoma

BH:

Bcl-2 homology

Mcl-1:

Myeloid cell leukaemia-1

IL-3:

Interleukin3

3-MA:

3-Methyladenine

CQ:

Chloroquine

Z-VAD:

Z-Val-Aal-DL-Asp-FMK

TRAIL:

Tumor necrosis factor related apoptosis-inducing ligand

RNase L:

Ribonuclease L

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Acknowledgments

The research was supported by the National Natural Science Foundation of China (Grant numbers: 81372793, 81272876 and 81202552).

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    Authors and Affiliations

    1. Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China

      Xiaoning Li, Jing Su, Hongyan Li, Chunhui Ma, Liwei Ma, Jingsong Kang & Liankun Sun

    2. Department of Obstetrics and Gynecology, Jilin University First Hospital, Changchun, 130021, China

      Meihui Xia

    3. Medical Research Laboratory, Jilin Medical College, Jilin, 132013, China

      Ye Xu

    4. Department of Pathogenic Microorganisms, Basic Medical College, Jilin University, Changchun, 130021, China

      Huimei Yu

    5. State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116012, Liaoning, China

      Zhichao Zhang

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    1. Xiaoning Li
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    Correspondence to Liankun Sun.

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    Xiaoning Li and Jing Su contributed equally to this study.

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    Li, X., Su, J., Xia, M. et al. Caspase-mediated cleavage of Beclin1 inhibits autophagy and promotes apoptosis induced by S1 in human ovarian cancer SKOV3 cells. Apoptosis 21, 225–238 (2016). https://doi.org/10.1007/s10495-015-1197-y

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