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Article

Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer

by
Donglin Yang
1,2,†,
Liujun He
1,*,†,
Shuiqing Ma
1,
Shiqiang Li
1,
Yajun Zhang
1,
Chunsheng Hu
1,
Jiuhong Huang
1,2,
Zhigang Xu
1,
Dianyong Tang
1 and
Zhongzhu Chen
1,*
1
College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing 402160, China
2
College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing 400715, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(7), 6662; https://doi.org/10.3390/ijms24076662
Submission received: 28 January 2023 / Revised: 19 March 2023 / Accepted: 27 March 2023 / Published: 3 April 2023
(This article belongs to the Special Issue Molecular Targets for Antiviral and Anticancer Drugs)
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Abstract

Compound 6d, a spiroindoline compound, exhibits antiproliferative capability against cancer cell lines. However, the exact underlying mechanism of this compound-mediated inhibitory capability remains unclear. Here, we showed that compound 6d is an inhibitor of Bcl-2, which suppresses CRC growth by inducing caspase 3-mediated intrinsic apoptosis of mitochondria. Regarding the underlying mechanism, we identified HDAC6 as a direct substrate for caspase 3, and caspase 3 activation induced by compound 6d directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound 6d promoted autophagy initiation by inhibiting interaction between Bcl-2 and Beclin 1, while it led to the accumulation of ubiquitinated proteins and the reduction of autophagic flux. Collectively, our findings reveal that the Bcl-2-caspase 3-HDAC6 cascade is a crucial regulatory pathway of autophagy and identify compound 6d as a novel lead compound for disrupting the balance between apoptosis and autophagy.
Keywords: compound 6d; colorectal cancer cells; Bcl-2; caspase 3; autophagy; HDAC6 compound 6d; colorectal cancer cells; Bcl-2; caspase 3; autophagy; HDAC6

Share and Cite

MDPI and ACS Style

Yang, D.; He, L.; Ma, S.; Li, S.; Zhang, Y.; Hu, C.; Huang, J.; Xu, Z.; Tang, D.; Chen, Z. Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer. Int. J. Mol. Sci. 2023, 24, 6662. https://doi.org/10.3390/ijms24076662

AMA Style

Yang D, He L, Ma S, Li S, Zhang Y, Hu C, Huang J, Xu Z, Tang D, Chen Z. Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer. International Journal of Molecular Sciences. 2023; 24(7):6662. https://doi.org/10.3390/ijms24076662

Chicago/Turabian Style

Yang, Donglin, Liujun He, Shuiqing Ma, Shiqiang Li, Yajun Zhang, Chunsheng Hu, Jiuhong Huang, Zhigang Xu, Dianyong Tang, and Zhongzhu Chen. 2023. "Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer" International Journal of Molecular Sciences 24, no. 7: 6662. https://doi.org/10.3390/ijms24076662

APA Style

Yang, D., He, L., Ma, S., Li, S., Zhang, Y., Hu, C., Huang, J., Xu, Z., Tang, D., & Chen, Z. (2023). Pharmacological Targeting of Bcl-2 Induces Caspase 3-Mediated Cleavage of HDAC6 and Regulates the Autophagy Process in Colorectal Cancer. International Journal of Molecular Sciences, 24(7), 6662. https://doi.org/10.3390/ijms24076662

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