# Roles for Intracellular pH Dynamics in Cancer Cell Behaviors

> **NIH NIH SC3** · SAN JOSE STATE UNIVERSITY · 2020 · $109,844

## Abstract

Project Summary
 Constitutively increased intracellular pH (pHi) is common to most cancers regardless of
tissue origin or genetic background. Increased pHi is necessary for survival of patient-derived
tumor cells, and is sufficient to induce oncogenic phenotypes, including dysregulated tissue
growth, dysplasia, and invasive cell migration. pH-regulated cell behaviors are predominantly
mediated by changes in the protonation state of pH sensitive proteins, or pH sensors, which is
viewed as a post-translational modification which cannot be resolved by mass spectrometry or
antibodies. At the molecular level, changes in pHi can alter the protonation state of selective
amino acid residues with pKa values near neutral, which can markedly affect protein
conformations and function. By changing the protonation of multiple proteins in unison, pHi
dynamics can coordinate complex cell processes. Although understudied, emerging evidence
suggests that the higher pHi of most cancers contributes to pathogenesis.
 In this proposal, we will characterize pH sensitive cancer cell behaviors and identify pH
sensors that regulate proliferation (Aim 1), programmed cell death (Aim 2) and metastasis (Aim
3). Using the genetic model organism Drosophila, we will bridge scales from tissue-level
phenotypic analyses to individual pH-sensitive proteins that regulate these cancer cell behaviors.
We will use cutting edge technologies including fluorescent cell cycle and apoptosis markers,
genetically encoded pH bio-sensors, and quantitative imaging techniques to generate 3-D maps
of intratumoral pHi. Our unpublished data with genetic modifier screens identified a number of
candidate pH sensors with known roles in regulating these processes. We will test predictions on
the pH-sensitive function of these candidate pH sensors.
 Significant outcomes from our studies include new insights on how pH-regulated cellular
behaviors enable tumorigenesis and metastasis. The strengths of the PI in linking tissue-level
phenotypes to individual pH-sensitive molecules permit unique insights in this under-studied area
of biology. Further, understanding the molecular mechanisms of pH-sensitive proteins will inform
novel therapeutic approaches to limit cancer progression.

## Key facts

- **NIH application ID:** 9951065
- **Project number:** 5SC3GM132049-02
- **Recipient organization:** SAN JOSE STATE UNIVERSITY
- **Principal Investigator:** Bree K. Grillo-Hill
- **Activity code:** SC3 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $109,844
- **Award type:** 5
- **Project period:** 2019-06-11 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9951065

## Citation

> US National Institutes of Health, RePORTER application 9951065, Roles for Intracellular pH Dynamics in Cancer Cell Behaviors (5SC3GM132049-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9951065. Licensed CC0.

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