Nuclear Factor Erythroid 2-Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression.

Abstract

As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated aldehyde dehydrogenase 3a1 (ALDH3A1) in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers. SIGNIFICANCE STATEMENT: We identified nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target aldehyde dehydrogenase 3a1 (ALDH3A1) as novel therapeutic targets in pancreatic cancer. They negatively affect the efficacy of a conventional chemotherapeutic agent, gemcitabine. We confirmed that Nrf2 plays a pivotal role in the induction of ALDH3A1.

• Authors: Ryotaro Matsumoto, Shin Hamada, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, Atsushi Masamune
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 379 Issue 1 Pg. 33-40 (10 2021) ISSN: 1521-0103 [Electronic] United States
• PMID: 34321315 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Antimetabolites, Antineoplastic
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Piperidines
• Quinazolinones
• Deoxycytidine
• ALDH3A1 protein, human
• Aldehyde Dehydrogenase
• halofuginone
• Gemcitabine

Topics

• Aldehyde Dehydrogenase (antagonists & inhibitors, metabolism)
• Animals
• Antimetabolites, Antineoplastic (pharmacology, therapeutic use)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, pharmacology, therapeutic use)
• Dose-Response Relationship, Drug
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• NF-E2-Related Factor 2 (antagonists & inhibitors, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Piperidines (pharmacology, therapeutic use)
• Quinazolinones (pharmacology, therapeutic use)
• Gemcitabine