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Bcl-2 的药理学靶向作用诱导 Caspase 3 介导的 HDAC6 切割并调节结直肠癌中的自噬过程。

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

机构信息

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.

College of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing 400715, China.

出版信息

Int J Mol Sci. 2023 Apr 3;24(7):6662. doi: 10.3390/ijms24076662.

DOI:10.3390/ijms24076662
PMID:37047634
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10095469/
Abstract

Compound , 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 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 directly cleaves HDAC6 into two fragments. Moreover, the cleavage site was located at D1088 in the DMAD-S motif HDAC6. Apoptosis stimulated by compound 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 as a novel lead compound for disrupting the balance between apoptosis and autophagy.

摘要

化合物是一种螺环吲哚啉化合物，对癌细胞系具有抗增殖能力。然而，该化合物介导的抑制能力的确切潜在机制尚不清楚。在这里，我们表明化合物是 Bcl-2 的抑制剂，它通过诱导 caspase 3 介导的线粒体内在凋亡来抑制 CRC 的生长。关于潜在机制，我们鉴定出 HDAC6 是 caspase 3 的直接底物，化合物诱导的 caspase 3 激活可将 HDAC6 直接切割成两个片段。此外，切割位点位于 DMAD-S 基序 HDAC6 中的 D1088。化合物诱导的细胞凋亡通过抑制 Bcl-2 与 Beclin 1 之间的相互作用来促进自噬的起始，同时导致泛素化蛋白的积累和自噬通量的减少。总之，我们的研究结果表明，Bcl-2-caspase 3-HDAC6 级联是自噬的关键调节途径，并确定化合物是破坏细胞凋亡和自噬之间平衡的新型先导化合物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d9a9/10095469/0c942f8c8911/ijms-24-06662-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d9a9/10095469/18c3d5f5ebbb/ijms-24-06662-g002.jpg
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