# Targeted inhibition of eIF5Ahpu suppresses tumor growth and M2-like TAM polarization in oral cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $469,285

## Abstract

PROJECT SUMMARY
Oral squamous cell carcinoma (OSCC) is the most common type of head & neck cancer and the 10th most
frequent human malignancy worldwide. Over the last several decades, the overall survival rate of OSCC patients
has stagnated between 40~55% despite some progress in diagnosis and therapy. The invasive growth or
progression of OSCC relies on the aggressiveness of cancer cells and their unique microenvironment, whereby
cancer stem cells (CSCs) and infiltrated tumor associated macrophages (TAMs) play pivotal roles. Previous
studies have demonstrated that polyamines (PA) are commonly elevated in tumor microenvironment (TME) and
have long been proven to be necessary for transformation and progression of various types of cancers. eIF5A2,
an isoform of a highly conserved translational factor, is overexpressed in many types of cancer. Remarkably,
spermidine-mediated eIF5A hypusination (eIF5Ahpu) that is implemented by two highly specialized enzymes,
deoxyhypusine synthase (DHS/DHPS) and deoxyhypusine hydroxylase (DOHH), appears to be essential to most,
if not all, of eIF5A’s biological functions, including its important role in regulating cancer cell proliferation,
epithelial-mesenchymal transition (EMT), and CSC properties as well as immune cell functions, thus rationally
emerging as a potential target for both therapy and prevention of cancer. Our analysis of TCGA dataset indicated
an overall upregulation in the mRNA expression of eIF5A2 and several key enzymes involved in PA metabolism
in HNSCC, which was confirmed by Western blot and IHC studies. Our studies showed that blocking
DHPS/eIF5Ahpu remarkably inhibited proliferation and CSC properties of OSCC cells, which correlated a
downregulation of TWIST1-BMI1 expression and NOTCH1/HES1 signaling. Meanwhile, we found that blocking
DHPS/eIF5Ahpu robustly inhibited OSCC-induced polarization of M2-like TAMs and reversed the
immunosuppressive effects conferred by OSCC-induced TAMs on T cell activation in vitro. More Importantly,
we found that blocking DHPS/eIF5Ahpu dramatically retarded tumor growth and infiltration/polarization of M2-like
TAM in an orthotopic syngeneic mouse tongue SCC model. Based on these compelling preliminary studies, we
hypothesize that eIF5Ahpu might play a critical role in OSCC growth and progression due to its dual functions in
regulating proliferation/CSC properties of OSCC cells and OSCC-induced M2-like TAM polarization. To test our
hypothesis, we propose three specific aims: 1) Elucidate mechanism by which eIF5Ahpu regulates proliferation
and CSC properties in OSCC; 2) Determine whether eIF5Ahpu plays a critical role in OSCC-induced polarization
of M2-like TAMs; 3) Target eIF5Ahpu to suppress tumor growth and immunosuppressive TAMs in OSCC in vivo.
New findings from this application might not only shed light on elucidating the function of eIF5Ahpu activation in
development and progression of OSCC, but also hold promises for identifying novel therapeutic targets fo...

## Key facts

- **NIH application ID:** 10441837
- **Project number:** 1R01DE031023-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Anh D Le
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $469,285
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441837

## Citation

> US National Institutes of Health, RePORTER application 10441837, Targeted inhibition of eIF5Ahpu suppresses tumor growth and M2-like TAM polarization in oral cancer (1R01DE031023-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10441837. Licensed CC0.

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