Most human tumors are either inherently insensitive to chemotherapy or acquire resistance upon relapse. Apoptosis is a major cytotoxic mechanism of chemotherapy, and defective apoptosis regulation in cancer cells contributes to therapeutic resistance. Apoptosis-based anticancer agents, such as BH3 and SMAC mimetics, have shown promising results in recent preclinical studies. However, the mechanisms of chemotherapy- induced apoptosis remain poorly understood. The agents in current clinical development have weak efficacy and limited applications due to their target limitations. Our long-term objective is to understand how apoptosis is initiated in human cancer cells, and develop more effective anticancer agents accordingly in a rational way. The ongoing studies have elucidated an essential role of PUMA, a BH3-only proapoptotic Bcl-2 family member, in chemotherapy-induced and p53-dependent apoptosis. Induction of PUMA by anticancer agents is often defective in cancer cells due to p53 deficiencies. Deletion of PUMA led to chemoresistance, and elevated PUMA expression elicited profound apoptotic and antitumor effects. These activities of PUMA are dependent upon its unique BH3 domain, and ability to induce mitochondrial dysfunction through the mitochondrial apoptogenic protein SMAC. Furthermore, PUMA is also activated by targeted anticancer drugs through p53- independent mechanisms. These observations suggest that the potent anticancer activities of PUMA, mediated by a unique BH3 domain structure and SMAC-regulated mitochondrial dysfunction, are broadly involved in anticancer therapy and can be manipulated to develop novel anticancer agents. This competitive renewal seeks to: 1) delineate the key determinants of the potent proapoptotic and antitumor activities of PUMA;2) determine the roles of PUMA and SMAC in modulating the response to targeted therapy;and 3) identify novel small-molecule PUMA inducers to kill p53-deficient cancer cells. These studies will provide new insight into the anticancer effects of chemotherapeutic agents. In the long run, the results of these studies may lead to improved therapeutic strategies and more effective anticancer agents.

Public Health Relevance

Deregulation in apoptosis is a hallmark of cancer and renders cancer cells resistant to anticancer therapy. This project seeks to understand the anticancer mechanisms of PUMA, an essential mediator of therapeutic response, and to identify novel agents that activate PUMA to kill cancer cells. The results will be useful for developing improved therapeutic strategies and more effective anticancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA106348-08
Application #
8257564
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Salnikow, Konstantin
Project Start
2004-04-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$262,120
Indirect Cost
$87,339
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Song, X; Kim, S-Y; Zhang, L et al. (2014) Role of AMP-activated protein kinase in cross-talk between apoptosis and autophagy in human colon cancer. Cell Death Dis 5:e1504
Chen, Dongshi; Wei, Liang; Yu, Jian et al. (2014) Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. Clin Cancer Res 20:3472-84
Sun, Jing; Knickelbein, Kyle; He, Kan et al. (2014) Aurora kinase inhibition induces PUMA via NF-?B to kill colon cancer cells. Mol Cancer Ther 13:1298-308
Kim, Seog-Young; Song, Xinxin; Zhang, Lin et al. (2014) Role of Bcl-xL/Beclin-1 in interplay between apoptosis and autophagy in oxaliplatin and bortezomib-induced cell death. Biochem Pharmacol 88:178-88
Chen, Xiaojun; Meng, Jie; Yue, Wen et al. (2014) Fibulin-3 suppresses Wnt/?-catenin signaling and lung cancer invasion. Carcinogenesis 35:1707-16
He, Kan; Zheng, Xingnan; Zhang, Lin et al. (2013) Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax. Mol Cancer Ther 12:2559-68
Qiu, W; Wang, X; Buchanan, M et al. (2013) ADAR1 is essential for intestinal homeostasis and stem cell maintenance. Cell Death Dis 4:e599
Zhang, Lin; Yu, Jian (2013) Role of apoptosis in colon cancer biology, therapy, and prevention. Curr Colorectal Cancer Rep 9:
Peng, R; Tong, J-S; Li, H et al. (2013) Targeting Bax interaction sites reveals that only homo-oligomerization sites are essential for its activation. Cell Death Differ 20:744-54

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