Role of P2X4 receptors in golgi PH regulation in pancreatic cancer
Active Project Grant Awarded Last action
- Award ID
- F31CA318249
- Recipient
-
Sanford Burnham Prebys Medical Discovery Institute UEI PHMKYKKJLQS1
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $93,428
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Originally
- Place of performance
- La Jolla, CA 92037, USA
Award details come from USAspending.gov.
Description
- Abstract
- Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, in part because IT CO- opts core cellular processes to support its growth and evade intervention. One such adaptation is the ability of PDAC cells to maintain an alkaline intracellular PH (PHI), which supports proliferation, survival, and metastasis despite the acid load generated by high metabolic activity. While much attention has been given to plasma membrane transporters that extrude protons, less is known about how internal organelles contribute to PH homeostasis. Emerging evidence suggests that acidic compartments like lysosomes and the golgi play a central role by buffering intracellular protons. To uncover cancer- specific mechanisms of PHI regulation, we performed a high-throughput chemical screen using a ratiometric golgi-targeted PH probe. This led to the identification an inhibitor of P2X4, which is an ATP- gated ION channel expressed in PDAC. We found that pharmacological inhibition or genetic depletion of P2X4 disrupts golgi acidification, decreases PHI, and selectively reduces viability in PDAC cells while sparing normal cells. These findings point to a novel role for P2X4 in maintaining intracellular PH through golgi function, an unexpected vulnerability that could be leveraged for therapeutic gain. We hypothesize that P2X4-mediated cation flux is required to maintain golgi acidification, and targeting this mechanism disrupts PHI homeostasis and tumor cell fitness. In aim 1, we will define the mechanism by which P2X4 regulates golgi PH in PDAC. We will also determine whether P2X4 regulates the PH of other intracellular organelles such as lysosomes. In aim 2, we will evaluate the therapeutic potential of P2X4 inhibition in preclinical PDAC mouse models. We will also evaluate the potential synergy of P2X4 inhibitors with standard-of-care chemotherapies and mechanism-specific compounds in vivo. By uncovering a previously unrecognized role for P2X4 in PH regulation and linking IT to cancer cell survival, this work could open new avenues for therapeutic intervention in a disease with few effective treatment options.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $46,714 | |
| Original award | $0 |
Quick answers
Who received award F31CA318249?
F31CA318249 was awarded to Sanford Burnham Prebys Medical Discovery Institute by National Cancer Institute (National Institutes of Health) on February 18, 2027.
How much is award F31CA318249 worth?
$93,428 has been obligated on F31CA318249.
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