# Adaptation to Extracellular Acidosis by pH-Sensing eIF5A

> **NIH NIH F30** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2021 · $48,883

## Abstract

Project Summary
System-wide remodeling of protein synthesis is an important component of cellular stress adaptation. Recent,
important studies support the observation that global translational adaptations (e.g. translation efficiency
remodeling and alternative translation machineries) often predominate over transcriptional control and mRNA
levels in controlling protein output. This phenomenon has been observed during evolution, development,
differentiation, and especially during cellular adaptations to physiological stimuli. Acidification of the extracellular
environment (extracellular acidosis) as a consequence of anaerobic metabolism is frequently observed in
tumors. We, and others, have shown that extracellular acidosis induces cancer cell dormancy, an enigmatic
phenotype involved in ischemic tolerance and cancer resistance to radiation and chemotherapy. An important
question remains regarding: what are the sensing mechanisms and assets that enable translational adaptations
in cells responding to variations in extracellular pH. Using our newly-developed, unbiased, biological activity-
based MATRIX platform, I introduce in this grant proposal the “Acidotic Protein Synthesis Machinery”. Amongst
the acidosis-enriched translation factors identified by MATRIX, eIF5A is, interestingly, the only one that can be
traced back to the last universal common ancestor, which is believed to have relied exclusively on anaerobic
metabolism. I will provide evidence that eIF5A operates as a pH-sensing transducer that is essential for the
specialized protein synthesis machinery that facilitates acidosis-induced tumor cell dormancy. I will reveal unique
acidosis-specific biomarkers derived from human cancer cell lines. Based on these preliminary data, I
hypothesize that eIF5A is a pH-sensing transducer that drives tumor cell adaptation to acidosis via
translatome reprogramming. We plan to test this hypothesis with the following specific aims: 1- Uncovering
the adaptive, acidosis-specific translatome; 2- Characterize the role of eif5A in cellular adaptation to acidosis.
Extracellular acidosis is a frequent but largely unexplored stimulus observed in an array of pathological settings,
including cancerous tumor microenvironments. The proposal is innovative as it will discover: 1- an extracellular
pH-sensing protein synthesis machinery, 2- an essential function in acidotic human cancer cells for the ancient
eIF5A, 3- the translatome of cancer cells responding to variations in extracellular pH, 4- panel(s) of acidosis-
specific protein markers that can be used to diagnose and/or prognose the acidotic state in experimental and
human clinical samples; and 5- mechanisms of cellular dormancy involved in ischemic tolerance and resistance
to mainstay anti-cancer therapy.

## Key facts

- **NIH application ID:** 10180918
- **Project number:** 5F30CA243268-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Nathan Charles Balukoff
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,883
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180918

## Citation

> US National Institutes of Health, RePORTER application 10180918, Adaptation to Extracellular Acidosis by pH-Sensing eIF5A (5F30CA243268-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10180918. Licensed CC0.

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