Abstract
Dichloroacetate (DCA), a traditional mitochondria-targeting agent, has shown promising prospect as a sensitizer in fighting against malignancies including cervical cancer. But it is unclear about the effect of DCA alone on cervical tumor. Moreover, previous reports have demonstrated that the increased cyclooxygenase-2 (COX2) expression is associated with chemoresistance and poor prognosis of cervical cancer. However, it is still unknown whether COX2 can affect the sensitivity of DCA in cervical cancer cells. In this study, we found that cervical cancer cells were insensitive to DCA. Furthermore, we for the first time revealed that DCA could upregulate COX2 which impeded the chemosensitivity of DCA in cervical cancer cells. Mechanistic study showed that DCA reduced the level of RNA binding protein quaking (QKI), leading to the decay suppression of COX2 mRNA and the subsequent elevation of COX2 protein. Inhibition of COX2 using celecoxib could sensitize DCA in repressing the growth of cervical cancer cells both in vitro and in vivo. These results indicate that COX2 is a novel resistance factor of DCA, and combination of celecoxib with DCA may be beneficial to the treatment of cervical cancer.
Highlights
Worldwide, cervical cancer is the second most common malignancy of women and is a major cause of morbidity and mortality [1]
DCA can reverse mitochondrial dysfunction and reactivate mitochondriadependent apoptosis in several tumor cells by inhibiting the activity of pyruvate dehydrogenase kinase (PDK), which subsequently promotes the flux of carbohydrates into mitochondria and thereby enhances aerobic oxidation of glucose [8, 10,11, 37,38]
In the present study, we found that DCA could suppress the growth of cervical cancer cells only at a high concentration, indicating that DCA is relatively ineffective in cervical cancer cells, unlike it shows in other cancer types
Summary
Cervical cancer is the second most common malignancy of women and is a major cause of morbidity and mortality [1]. Platinum and taxol-based chemotherapies are still standard paradigms in addition to surgery, but their side effects are severe and the chemoresistance has emerged [2,3,4,5]. It is urgent to explore novel strategies as alternatives of traditional chemotherapy. There are growing evidences that the unique metabolism is a new essential target of most solid tumors. Targeting key metabolic pathways can significantly kill numerous cancer cells including cervical cancer cells [6,7]. Dichloroacetate (DCA) has shown charming prospect because of its positive function in cancer therapy
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