Dihydroartemisinin Enhances the Effects of Oxaliplatin by Activating PDCD5/ARAF mediated Signal Transduction in Colon Cancer

Abstract

Abstract Programmed cell death 5 (PDCD5) has been reported to be expressed at low levels in various types of cancers and can be upregulated and rapidly migrate from the cytoplasm to the nucleus when cell death is induced. It is believed to be an important prognostic marker for the response to cancer therapy. Further study of the molecular mechanism by which PDCD5 exerts its antitumour activity and exploration of low toxicity and high-efficiency drugs targeting PDCD5 may reveal a promising strategy for clinical cancer therapy. In this study, the function and molecular mechanism of PDCD5 in colon tumorigenesis were thoroughly studied. PDCD5 was distributed mainly in nontumor tissues and expressed at low levels in colon cancer tissues, and the expression level of PDCD5 was negatively related to cell proliferation and tumour growth. In addition, PDCD5 expression was positively related to the cytotoxicity of oxaliplatin and dihydroartemisinin (DHA). The molecular mechanism of PDCD5 in colon tumorigenesis was also studied using proteomic analysis, which showed that PDCD5 can downregulate ARAF expression and subsequently impair ARAF/MEK/ERK signal transduction. DHA exerts its antitumour activity via active PDCD5 to suppress the ARAF/MEK/ERK signalling pathway and improve the antitumour effects of oxaliplatin. In summary, DHA can enhance the cytotoxic effects of oxaliplatin by regulating PDCD5 expression and subcellular localization to suppress the ARAF/MEK/ERK signalling pathway.