1. Academic Validation
  2. Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2-RCHY1 mediated signaling pathway

Dihydroartemisinin synergistically enhances the cytotoxic effects of oxaliplatin in colon cancer by targeting the PHB2-RCHY1 mediated signaling pathway

  • Mol Carcinog. 2022 Nov 7. doi: 10.1002/mc.23486.
Xiwei Wang 1 Yingying Zheng 2 3 Zhengbin Chai 4 Ji Li 5 Changhui Zhu 6 Yanling Peng 7 Juanjuan Qiu 7 Jiajun Xu 7 Chunyan Liu 3
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China.
  • 2 Shandong Provincial Key Laboratory for Rheumatic Disease and Translational Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China.
  • 3 Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, People's Republic of China.
  • 4 Department of Clinical Laboratory Medicine, Shandong Public Health Clinical Center, Jinan, People's Republic of China.
  • 5 Department of AIDS Control and Prevention, Center for Disease Control and Prevention of Jining, Jining, Shandong, People's Republic of China.
  • 6 School of Basic Medicine, Weifang Medical University, Weifang, Shandong, China.
  • 7 Shandong First Medical University & Shandong First Medical University, Jinan, People's Republic of China.
Abstract

Dihydroartemisinin (DHA) has recently attracted increasing attention for its low toxicity and high antitumor activity. DHA has been reported to have synergistic Anticancer effects with a variety of drugs in the clinic; however, the molecular mechanism by which DHA inhibits tumorigenesis and improves oxaliplatin cytotoxicity in colon Cancer cells is still not well understood. In this study, we found that DHA can inhibit cell proliferation and colony formation in a dose-dependent manner. Prohibitin 2 (PHB2) is a potential target by which DHA exerts its antitumor and cytotoxic effects. The function and molecular mechanism of PHB2 in colon Cancer tumorigenesis were fully studied to determine the regulatory mechanism between DHA and PHB2. We found that PHB2, a mitochondrial inner membrane scaffold protein, has a higher expression level in colon Cancer tissues than in adjacent nontumor tissues and is mainly localized in mitochondria. Overexpression of PHB2 can promote cell proliferation and colony formation in vitro and accelerate tumor growth in vivo. We also found that the expression level of PHB2 was inversely related to the cytotoxicity of DHA and oxaliplatin in colon Cancer cells. The molecular mechanism of PHB2 in tumorigenesis and Cancer therapy was further studied. The results showed that 20 μM DHA can downregulate PHB2 expression in a ubiquitylation-dependent manner and subsequently block PHB2-induced RCHY1 upregulation and p53 and p21 downregulation. In this process, RCHY1 is necessary for PHB2 to play a tumor-promoting role. Thus, PHB2 and RCHY1 are effective targets for colon Cancer therapy, and DHA has synergistic Anticancer effects with oxaliplatin via promoting PHB2 degradation in colon Cancer cells.

Keywords

DHA; PHB2; RCHY1; colon cancer; oxaliplatin.

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