1. Academic Validation
  2. Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer

Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer

  • Cell Death Dis. 2021 May 14;12(5):490. doi: 10.1038/s41419-021-03771-z.
Asmat Ullah 1 Sze Wei Leong 2 Jingjing Wang 1 Qing Wu 1 Mohsin Ahmad Ghauri 1 Ammar Sarwar 1 Qi Su 3 Yanmin Zhang 4
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.
  • 2 Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Seri Kembangan, Malaysia.
  • 3 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China. suqi201803@mail.xjtu.edu.cn.
  • 4 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China. zhang2008@mail.xjtu.edu.cn.
Abstract

Lung Cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including Reactive Oxygen Species (ROS) production, Carbonic Anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.

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