Projects and Grants per year
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Description
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.
Status | Active |
---|---|
Effective start/end date | 4/1/09 → 4/30/25 |
Funding
- National Cancer Institute
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Projects
- 1 Active
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The Role of PHLPP in Colon Cancer
Gao, T. (PI), St Clair, D. (CoI) & Weiss, H. (CoI)
4/1/09 → 4/30/25
Project: Research project