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

Jian Li, Cheng Hsun Chen, Katelyn L. O'Neill, Valerie J. Fousek-Schuller, Adrian R. Black, Jennifer D. Black, Jingjing Zhang, Xu Luo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number102875
JournalJournal of Biological Chemistry
Volume299
Issue number2
DOIs
StatePublished - Feb 2023

Keywords

  • BH3-mimetics
  • Bcl-2 family
  • apoptosis
  • aurora kinase inhibitor
  • aurora kinases
  • caspases

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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