Combined inhibition of aurora kinases and Bcl-xL induces apoptosis through select BH3-only proteins.

Autor:	Li J; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA., Chen CH; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA., O'Neill KL; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA., Fousek-Schuller VJ; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA., Black AR; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA., Black JD; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA., Zhang J; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA., Luo X; Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, Omaha, Nebraska, USA; Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA. Electronic address: xuluo@unmc.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2023 Feb; Vol. 299 (2), pp. 102875. Date of Electronic Publication: 2023 Jan 06.
DOI:	10.1016/j.jbc.2023.102875
Abstrakt:	Aurora kinases (AURKs) are mitotic kinases important for regulating cell cycle progression. Small-molecule inhibitors of AURK have shown promising antitumor effects in multiple cancers; however, the utility of these inhibitors as inducers of cancer cell death has thus far been limited. Here, we examined the role of the Bcl-2 family proteins in AURK inhibition-induced apoptosis in colon cancer cells. We found that alisertib and danusertib, two small-molecule inhibitors of AURK, are inefficient inducers of apoptosis in HCT116 and DLD-1 colon cancer cells, the survival of which requires at least one of the two antiapoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1. We further identified Bcl-xL as a major suppressor of alisertib- or danusertib-induced apoptosis in HCT116 cells. We demonstrate that combination of a Bcl-2 homology (BH)3-mimetic inhibitor (ABT-737), a selective inhibitor of Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib potently induces apoptosis through the Bcl-2 family effector protein Bax. In addition, we identified Bid, Puma, and Noxa, three BH3-only proteins of the Bcl-2 family, as mediators of alisertib-ABT-737-induced apoptosis. We show while Noxa promotes apoptosis by constitutively sequestering Mcl-1, Puma becomes associated with Mcl-1 upon alisertib treatment. On the other hand, we found that alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into truncated Bid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Published by Elsevier Inc.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu