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

by Selleckchem | Nov 08 2023

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.

Comments:

The passage you provided discusses a research study that focuses on the role of Bcl-2 family proteins in inducing apoptosis (programmed cell death) in colon cancer cells using small-molecule inhibitors of Aurora kinases (AURKs). Here's a breakdown of the key findings and implications of the study:

1. Aurora Kinases (AURKs) and Cancer: Aurora kinases are essential mitotic kinases that regulate cell cycle progression. Inhibitors of AURK have shown promising effects in treating multiple cancers.

2. Limited Induction of Cancer Cell Death: However, the effectiveness of AURK inhibitors in inducing cancer cell death (apoptosis) has been limited.

3. Bcl-2 Family Proteins: The study examines the role of Bcl-2 family proteins in AURK inhibitor-induced apoptosis in colon cancer cells.

4. Inefficiency of AURK Inhibitors Alone: The small-molecule inhibitors of AURK, alisertib, and danusertib, were found to be inefficient inducers of apoptosis in HCT116 and DLD-1 colon cancer cells.

5. Bcl-xL and Mcl-1 as Survival Factors: The survival of these colon cancer cells depends on at least one of the two antiapoptotic Bcl-2 family proteins, Bcl-xL and Mcl-1.

6. Bcl-xL Suppression: Bcl-xL was identified as a major suppressor of apoptosis induced by alisertib or danusertib in HCT116 cells.

7. Combination Therapy: The researchers combined a BH3-mimetic inhibitor called ABT-737, which targets Bcl-xL, Bcl-2, and Bcl-w, with alisertib or danusertib. This combination proved to be potent in inducing apoptosis through the Bcl-2 family effector protein Bax.

8. Mediators of Apoptosis: Three BH3-only proteins of the Bcl-2 family, namely Bid, Puma, and Noxa, were identified as mediators of apoptosis induced by the combination of alisertib and ABT-737.

9. Noxa and Mcl-1 Interaction: Noxa promotes apoptosis by binding and sequestering Mcl-1.

10. Puma and Mcl-1 Interaction: Puma becomes associated with Mcl-1 upon alisertib treatment, presumably leading to apoptosis.

11. Caspase-2 Activation: Alisertib treatment causes the activation of caspase-2, which cleaves Bid into truncated Bid. This truncated Bid acts as a suppressor of both Bcl-xL and Mcl-1, further promoting apoptosis.

12. Overcoming Resistance: These results indicate that the Bcl-2 protein network plays a critical role in AURK inhibitor-induced apoptosis, and using BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells.

In summary, the study highlights the importance of Bcl-2 family proteins in regulating the effectiveness of AURK inhibitors in inducing apoptosis in colon cancer cells. By combining AURK inhibitors with BH3-mimetics targeting Bcl-xL, it may be possible to enhance the apoptotic response and potentially overcome resistance to AURK inhibitors in cancer treatment.