Dichloroacetate Overcomes Oxaliplatin Chemoresistance in Colorectal Cancer through the miR-543/PTEN/Akt/mTOR Pathway

Abstract

Chemoresistance is responsible for most colorectal cancer (CRC) related deaths. In this study, we found that dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, can be used as a sensitizer for oxaliplatin (L-OHP) chemoresistant CRC cells. The aim of this study was to explore the ability of DCA to overcome L-OHP resistance in CRC cells and to identify the underlying molecular mechanisms. We found that DCA sensitizes chemoresistant CRC cells to L-OHP-induced cytotoxic effects by inhibiting clone formation capacity and promoting cell apoptosis. A microRNA (miRNA) array was used for screen, and miR-543 was identified and shown to be downregulated after DCA treatment. The expression of miR-543 was higher in chemoresistant CRC cells than in chemosensitive CRC cells. Overexpression of miR-543 increased chemoresistance in CRC cells. The validated target gene, PTEN, was negatively regulated by miR-543 both in vitro and in vivo, and PTEN was upregulated by DCA through miR-543. In addition, overexpression of miR-543 reversed the inhibition of colony formation after DCA treatment. Furthermore, the Akt/mTOR pathway is activated by miR-543 and is involved in the miR-543 induced chemoresistance. There was a significant inverse relationship between miR-543 expression and PTEN level in CRC patients, and high miR-543 expression was associated with worse prognosis. In conclusion, DCA restored chemosensitivity through miR-543/PTEN/Akt/mTOR pathway, and miR-543 may be a potential marker or therapeutic target for chemoresistance in CRC.

Glycolysis-induced drug resistance in tumors—A response to danger signals?

“…In fact, apoptosis is the main mechanism for tumor cell death in response to antitumor drugs and, therefore, a molecule that induces drug resistance is expected to have antiapoptotic effects. Antiapoptotic effects have been demonstrated for glycolytic metabolism in general [49 , 98 , 112] and for individual components of it: enzymes like HK2 [16] , PFKFB3 [49] , PFK platelet type P (PFKP) [121] , ENO1 [56 , 95] , PKM2 [18 , 59 , 94 , 109 , 122] , LDHA [123] , PDK isoform 1 (PDK1) [73 , 124] , metabolites like pyruvate [78] , lactate and lactate-induced acidosis [87] . Antiapoptotic effects are achieved in several ways.…”

Diethyldithiocarbamate-copper complex (CuET) inhibits colorectal cancer progression via miR-16-5p and 15b-5p/ALDH1A3/PKM2 axis-mediated aerobic glycolysis pathway

“…For example, metformin for diabetes is effective for pancreatic cancer, lung cancer, and ovarian cancer 35 – 37 ; aspirin for cardiovascular diseases is effective for hepatocellular carcinoma, prostate cancer, and gastric cancer etc 38 – 40 . Notably, we recently found that dichloroacetate (DCA), which was originally used to treat lactic acidosis, hereditary mitochondrial metabolism disorder and diabetes, may restore chemosensitivity in CRC cells 41 – 43 . Therefore, it is valuable to explore the pharmacological effects of existing drugs for saving medical resources, improving the life span and quality of life of patients by repurposing traditional drugs.…”

Small in Size, but Large in Action: microRNAs as Potential Modulators of PTEN in Breast and Lung Cancers

“…The interesting point is that anti-tumor compounds including cryptotanshinone suppress cancer proliferation and induce apoptosis via PTEN upregulation and the subsequent inhibition of PI3K/Akt/mTOR and nuclear factor-kappaB (NF-ĸB) pathways [ 89 ]. Dichloroacetate can suppress chemoresistance in cancer cells via the downregulation of miRNA-543, upregulation of PTEN, and inhibition of the PI3K/Akt axis [ 90 ]. EMT is associated with the metastasis of cancer cells [ 81 , 91 ].…”