Grants and Contracts per year
Grants and Contracts Details
Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Approximately 145,000 new cases and 51,000 deaths are predicted for the year 2019; and this mortality is predominantly due to poor responses to available treatment options. A better understanding of the molecular events leading to cancer progression and chemoresistance is needed in order to improve the overall survival of cancer patients. My lab has been intensively focused on elucidating the role of a novel family of protein phosphatases, PHLPP (PH domain Leucine-rich-repeats Protein Phosphatase), in inhibiting colon cancer initiation and progression. We have made substantial progress in understanding the functional importance of PHLPP as a tumor suppressor as well as the molecular mechanism underlying PHLPP regulation. The overall objective of this study is to further develop a mechanistic understanding of PHLPP-mediated regulation of cellular stress response in supporting cell survival and tumorigenesis. In exciting recent findings, we demonstrated that chemotherapy-induced ER stress promotes PHLPP degradation and PHLPP-loss provides a survival advantage by upregulating eIF2α/ATF4-mediated signaling. In addition, we found that downregulation of PHLPP promotes mitochondrial fission by regulating Drp1 phosphorylation. Collectively, the central hypothesis driving this proposed study is that PHLPP serves an essential stress sensor in CRC, in which cellular stress signals trigger PHLPP degradation to promote cell survival and tumorigenesis. The following specific aims are proposed: 1) to delineate the molecular mechanism underlying PHLPP-mediated regulation of eIF2α/ATF4 signaling. We will determine if downregulation of PHLPP renders colon cancer cells resistant to chemotherapy drugs as a result of autophagy activation; 2) to determine the functional importance of PHLPP-mediated regulation of mitochondrial dynamics; and 3) to define the role of mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis in vivo. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes to tumor initiation and progression in colon cancer. This supplement will allow Ms. Carolina Galeano-Naranjo to receive further training in conducting basic and translational cancer research. Her results will assist in determining the role of PHLPP in CRC by regulating mitochondrial activity. She will determine if PHLPP mutations found in CRC patients interfer with their ability to control Drp1 phosphorylation and mitochondrial fission. Ultimately, by providing mechanistic insights into PHLPP-dependent regulation of stress response, our findings will help identify new treatment options and better predict the effectiveness of chemotherapy agents based on PHLPP status in cancer patients.
|Effective start/end date||4/1/09 → 4/30/25|
- National Cancer Institute
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