# The Functional Role of GRM3 in Colon Cancer

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $356,850

## Abstract

Colorectal cancer is the second leading cause of cancer mortality in the US, in part due
to the lack of effective therapies for advanced disease. Thus, there is an urgent need to identify
molecules/pathways involved in colon cancer development and metastasis for cancer treatment.
 Glutamate is an essential amino acid that plays important roles in signaling as a major
neurotransmitter in mammalian central nervous system (CNS). Glutamate signaling is mediated
by glutamate receptors. GRM3 is one of the group II metabotropic glutamate receptors. The
glutamatergic system is mainly restricted to the CNS. However, it has been recently shown that
GRM3 is frequently mutated in melanoma and that mutant GRM3 increased anchorage-
independent growth and migration of melanoma cells. In addition, activation of GRM3 has been
reported to sustain tumorigenic potential of glioma-initiating cells. Pharmacological blockade of
GRM3 reduced growth of glioma cells in vitro and in vivo. These studies suggest that GRM3
may play a role in cancer. Our preliminary data showed that expression of GRM3 is significantly
elevated in more than 90% of colon cancer specimens examined. Knockdown of GRM3 in colon
cancer cells suppresses cell survival and anchorage-independent growth in vitro and inhibits
tumor growth in a xenograft model in vivo. Mechanistically GRM3 inactivates protein kinase A
(PKA) and activates AKT. In addition, TGFβ increases GRM3 expression and that knockdown
of GRM3 enhances TGFβ-mediated tumor suppressor function. These studies suggest that
upregulation of GRM3 expression is a functionally important molecular event during colon
cancer development and progression. Therefore, GRM3 may play an important role in colon
cancer tumorigenesis and metastasis and could be a potential target for colon cancer treatment.
 In this proposal, we will investigate the mechanisms by which TGFβ regulates GRM3
expression and whether their crosstalk plays a role in colon cancer metastasis. We will also
determine GRM3 function in colon cancer using genetic mouse models and whether GRM3
contributes to development and/or maintenance of colon cancer metastasis using an orthotopic
mouse model. Furthermore, we will demonstrate the clinical relevance and significance of
elevated GRM3 in colon cancer patient samples. The completion of these studies will identify
TGFβ/GRM3/PKA as a novel signaling axis regulating colon cancer development and
progression and establish GRM3 as a potential therapeutic target for colon cancer treatment.

## Key facts

- **NIH application ID:** 10080029
- **Project number:** 5R01CA215389-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jing Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2017-03-14 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10080029

## Citation

> US National Institutes of Health, RePORTER application 10080029, The Functional Role of GRM3 in Colon Cancer (5R01CA215389-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10080029. Licensed CC0.

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