Graduation Date

Summer 8-12-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Interdisciplinary Graduate Program in Biomedical Sciences

First Advisor

Xu Luo

Second Advisor

Jixin Dong

Third Advisor

Adam Karpf

Fourth Advisor

Rakesh Singh

Abstract

Dysregulated apoptosis contributes to carcinogenesis and can lead to drug resistance, a hallmark of cancer. Most drug-induced apoptosis is dependent on the mitochondrial pathway, primarily regulated by the Bcl-2 family proteins. Dysregulation of the Bcl-2 family proteins such as an over-expression of the anti-apoptotic Bcl-2 proteins is known to cause drug resistance. In our first study, we identify the anti-apoptotic Bcl-2 protein, Bcl-xL, as a major suppressor of apoptosis induced by small molecule inhibitors of Aurora kinases (AURK), which have shown limited cell-killing effects in colorectal cancer cells. We found that a combination of a BH3-mimetic inhibitor, ABT-737, a selective inhibitor against the anti-apoptotic Bcl-2 proteins, in combination with AURK inhibitors Alisertib or Danusertib potently induces apoptosis in these cells. We, therefore, defined the Bcl-2 network, including the effector Bax and mediators BH3-only proteins Bid, Puma, and Noxa, that is critically involved in AURK inhibitor/ABT-737-induced apoptosis. These results provide new insights into overcoming resistance to AURK inhibitors in cancer cells. Besides overexpression of anti-apoptotic Bcl-2 family proteins in cancer cells, another common mechanism that renders cancer cells resistant to apoptosis is the loss of the effector Bcl-2 family proteins Bax and Bak. In our second study, we found that such resistance can be overcome by inhibition of the proteasome. Proteasome is essential for numerous cellular functions, and its inhibition is mostly known to kill cancer cells through a mitochondrial apoptosis pathway. However, inhibition of the proteasome can also induce apoptosis in a Bax/Bak-independent manner. We identify a proteasome inhibition-induced, Bax/Bak-independent apoptotic pathway that involves the death ligand-independent activation of Death Receptor 5 and the inhibition of an inhibitor of caspases. Blocking both the Bax/Bak-dependent and Bax/Bak-independent pathways abolish proteasome inhibition-induced apoptosis. Together, my work indicates that resistance to the mitochondrial pathway of apoptosis can be overcome by multiple pharmacological treatments, therefore suggesting novel combinations of therapeutics against cancer.

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