Aldh2 deficiency plays a dual role in lung tumorigenesis and tumor progression.
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ABSTRACT:
SUBMITTER: Zhang H
PROVIDER: S-EPMC10825233 | biostudies-literature | 2024 May
REPOSITORIES: biostudies-literature
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Aldh2 deficiency plays a dual role in lung tumorigenesis and tumor progression.
Zhang Hongjia H Sun Xueqian X Li Zhanming Z Liu Tingting T Zhang Fang F Meng Xinyu X Li Kaimi K Xu Jianhua J He Wei W Jing Bo B Wang Tong T Ni Na N Sun Beibei B Yao Feng F Wu Yadi Y Wang Qi Q Du Jing J Chin Eugene Y EY Zhou Binhua P BP Jiang Ping P Wang Lishun L Deng Jiong J
Genes & diseases 20230624 3
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Project description:The major role of aldehyde dehydrogenase 2 family (ALDH2) is to detoxify acetaldehyde (ACE) to non-toxic acetic acid. Many evidences suggest that ALDH2 dysfunction contributes to a variety of human diseases including cancer. However, the biological function and molecular mechanism of ALDH2 in tumor progression remain elusive. In this study, we found that ALDH2 repression was associated with poor prognosis in lung adenocarcinoma. Overexpression of ALDH2 inhibited malignant features of lung adenocarcinoma cells, such as proliferation, stemness and migration, whereas ALDH2 knockdown increased these features. Mechanistically, ALDH2 repression led to accumulation of ACE; whereas ACE enhanced the migration features of lung adenocarcinoma cells, which was associated with increased DNA damage. Importantly, accumulated ACE and increased DNA damage were identified in Aldh2-knockout (KO) mouse lung tissues in vivo. Consistent with this concept, treatment of lung adenocarcinoma cells with ALDH2 agonist Alda-1 suppressed the proliferation, stemness and migration features of lung adenocarcinoma cells. Thus, activating ALDH2, such as via its agonist, may provide a novel strategy for treatment of lung cancer.
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Project description:Paraoxonase 2 (PON2) is a multifunctional intracellular enzyme that has received growing attention for its ability to modulate various aspects of normal and malignant cellular physiology. Recent research has revealed that PON2 is upregulated in tissues from patients with various types of solid tumors and hematologic cancers, likely due to its ability to suppress oxidative stress and evade apoptosis. However, the effects of PON2 on pulmonary oncogenesis are unknown. Here, we conducted studies to investigate how PON2 influences lung cancer cell proliferation in vitro and lung tumorigenesis in vivo using a variety of cellular and animal models. It was found that PON2 expression deficiency hampered the proliferation of cultured lung cancer cells with concomitant cell cycle arrest at the G1 phase. In addition, the loss of endogenous PON2 expression impaired key aspects of oxidative metabolism in lung adenocarcinoma cells. Moreover, we investigated how the interplay between PON2 expression in lung tumors and host mice influences lung tumor initiation and progression. PON2 status in both transplanted tumor cells and mice failed to influence the development of subcutaneously grafted Lewis lung carcinoma (LLC) tumors, orthotopically implanted LLC tumors, and oncogenic Kras-driven primary lung adenocarcinoma tumors. Importantly, the frequencies of tumor-infiltrating myeloid subsets that include myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages were not impacted by PON2 expression in LLC tumor-bearing mice. Overall, our studies indicate that PON2 plays a limited role in murine lung tumorigenesis.
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Project description:ALDH2 activator, Alda-1, is able to increase the catalytic activity of ALDH2. ALDH2 expression negatively correlates with obesity in mice while 4-HNE accumulation is positively associated with obesity and is increased in terminal adipocyte differentiation. We compared the difference of transcription profile between ethanol (EtOH)-treated and Alda-1-treated cells in induced adipocyte differentiation of 3T3-L1 pre-adipocytes.
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