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

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,

Essential Protein PHB2 and Its Regulatory Mechanisms in Cancer

“…Overexpression of PHB2 enhances colon cancer growth in vitro and in vivo. PHB2 was reported as a novel target of Dihydroartemisinin (DHA) in colon cancer [ 49 ]. DHA is an effective clinical drug for treatment of malaria, but it also has promising anticancer effects that have been tested in many cancers [ 66 ].…”

“…The proposed mechanism is through DHA inhibiting the expression of PHB2 in a ubiquitylation-dependent manner and reversing PHB2-induced RCHY1 (RING finger and CHY zinc finger domain-containing protein 1) expression, as well as suppressing p53 and p21 expression. Therefore, both PHB2 and RCHY1 are promising targets in colon cancer therapy [ 49 ].…”

“…PHB2 induces RCHY1 expression. DHA inhibits PHB2 and RCHY1 expression and suppresses p53 and p21 [ 49 ].…”

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

“…Cell proliferation activity was determined using the CCK8 assay according to a protocol described in a previous study [20]. In brief, 100 µL of cell suspension was plated into 96-well plates (5×10 3 /well for RKO cells, 8×10 3 /well for HCT116 cells) and incubated overnight.…”

“…DHA exerts its antitumour activity via various mechanisms, such as inhibiting proliferation, metastasis and angiogenesis and promoting apoptosis and immune function [2].Previous studies by our group and other groups reported that DHA can enhance the antitumour activity of a variety of chemotherapeutic drugs [3][4][5]. In our previous study, we found that DHA can enhance the cytotoxic effects of oxaliplatin in colon cancer [3]. However, the molecular mechanism by which DHA enhances antitumour activity is incompletely understood.…”