# Reduced reactive oxygen species and oxidative phosphorylation in arsenic-induced cancer stem cells

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2020 · $450,082

## Abstract

In our previous studies we had demonstrated that arsenic (As3+), an environmental metalloid metal, was able
to induce transformation of the human bronchial epithelial cells. Additional experimental data revealed presence
of cancer stem-like cells (CSCs) among the transformed cells induced by As3+. Other preliminary data showed
that: (i) The CSCs induced by consecutive low-concentration As3+ treatment of the human bronchial epithelial
cells exhibited significant decrease of reactive oxidative species (ROS) due to severe inhibition of the
mitochondrial oxidative phosphorylation (OXPHOS); (ii) As3+ induced JNK and STAT3 (pSTAT3S727)
phosphorylation in mitochondria along with a diminish of the mitochondrial transcription factor A (TFAM); (iii)
integrated transcriptomic and metabolomic analyses demonstrated a higher rate of glycolysis and lower levels
of mitochondrial metabolism due to mitochondrial DNA (mtDNA) depletion among these As3+-induced CSCs;
and (iv) a unique glycolytic feature that is different from naïve embryonic stem cells (ESCs) and cancer cells was
found in these As3+-induced CSCs. Both ESCs and cancer cells direct glycolysis for lactate production. In
contrast, the As3+-induced CSCs show increased conversion of the glycolytic intermediates into the subsidiary
pathways for the generation of N-acetylglucosamine important for O-GlcNAcylation of the stemness genes and
the S-adenosyl methionine (SAM) that contributes to DNA and histone methylation. Accordingly, the goal of this
application is to determine: (1) is As3+-induced JNK-dependent pSTAT3S727 responsible for the inhibition of
mitochondria; (2) if so, how this JNK-dependent pSTAT3S727 signaling pathway elicited by As3+ impairs the
integrity or function of mitochondria, such as mtDNA replication, transcription, OXPHOS, etc; and (3) how the
impaired function of mitochondria contributes to the generation of the CSCs induced by As3+. We hypothesize
that As3+-induced JNK-dependent pSTAT3S727 signaling promotes formation of the CSCs by inhibiting
mitochondrial OXPHOS and ROS generation, and the subsequent enhancement of glycolysis of the cells. To
test this hypothesis, the following three specific aims are proposed: Specific Aim 1: determine how As3+
activates mitochondrial JNK that phosphorylates STAT3 S727 (pSTAT3S727) in BEAS-2B and other lung cells for
the formation of CSCs. We will focus on the activation of mitochondrial-localized upstream kinases of JNK in
response to As3+. The JNK dependent phosphorylation of additional mitochondrial proteins will be investigated
through mitochondrial phosphoproteome; Specific aim 2: understand how As3+-induced JNK-dependent
pSTAT3S727 inhibits mitochondria by addressing the role of pSTAT3S727 in mtDNA binding, its interaction with the
mitochondrial transcription factor A (TFAM), and its effects on mitochondrial ROS production, proteome and the
cellular metabolomics in the As3+-treated cells and As3+-induced CSCs; Specific Aim 3: utilize our uniqu...

## Key facts

- **NIH application ID:** 9933053
- **Project number:** 5R01ES028263-04
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Fei Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,082
- **Award type:** 5
- **Project period:** 2017-08-15 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933053

## Citation

> US National Institutes of Health, RePORTER application 9933053, Reduced reactive oxygen species and oxidative phosphorylation in arsenic-induced cancer stem cells (5R01ES028263-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9933053. Licensed CC0.

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