# The Role of PHLPP in Colon Cancer

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $361,929

## Abstract

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.
We will test the hypothesis that PHLPP plays an important role in regulating mitochondrial dynamics by
enhancing Drp1 activity in order to cope with proinflammatory stress signals; and 3) to define the role of
mitochondrial dynamics in cooperating with PHLPP-loss to promote tumorigenesis in vivo. We will utilize Drp1
and PHLPP knockout mice to determine the function interaction between PHLPP and Drp1 on regulating colon
cancer tumorigenesis in vivo. Our proposed study centers on a novel hypothesis that that PHLPP-loss plays a
pivotal role in orchestrating multiple pro-survival responses downstream of cellular stress signals to promote
tumorigenesis. Our study will fill an important knowledge gap on how altered mitochondrial dynamics contributes
to tumor initiation and progression in colon cancer. 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...

## Key facts

- **NIH application ID:** 10068786
- **Project number:** 2R01CA133429-13A1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Tianyan Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $361,929
- **Award type:** 2
- **Project period:** 2009-04-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068786

## Citation

> US National Institutes of Health, RePORTER application 10068786, The Role of PHLPP in Colon Cancer (2R01CA133429-13A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10068786. Licensed CC0.

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