Cancer stem cells (CSCs) are a small subset of malignant cells, possessing stemness, with strong tumorigenic capability, conferring resistance to therapy and leading to the relapse of nasopharyngeal carcinoma (NPC). Our previous study suggested that cyclooxygenase-2 (COX-2) would be a novel target for the CSCs-like side population (SP) cells in NPC. In the present study, we further found that COX-2 maintained the stemness of NPC by enhancing the activity of mitochondrial dynamin-related protein 1 (Drp1), a mitochondrial fission mediator, by studying both sorted SP cells from NPC cell lines and gene expression analyses in NPC tissues. Using both overexpression and knockdown of COX-2, we demonstrated that the localization of COX-2 at mitochondria promotes the stemness of NPC by recruiting the mitochondrial translocation of p53, increasing the activity of Drp1 and inducing mitochondrial fisson. Inhibition of the expression or the activity of Drp1 by siRNA or Mdivi-1 downregulates the stemness of NPC. The present study also found that inhibition of mitochondrial COX-2 with resveratrol (RSV), a natural phytochemical, increased the sensitivity of NPC to 5-fluorouracil (5-FU), a classical chemotherapy drug for NPC. The underlying mechanism is that RSV suppresses mitochondrial COX-2, thereby reducing NPC stemness by inhibiting Drp1 activity as demonstrated in both the in vitro and the in vivo studies. Taken together, the results of this study suggest that mitochondrial COX-2 is a potential theranostic target for the CSCs in NPC. Inhibition of mitochondrial COX-2 could be an attractive therapeutic option for the effective clinical treatment of therapy-resistant NPC.

BackgroundHepatocellular carcinoma (HCC) remains a major public health problem worldwide. The identification of effective chemotherapeutic targets for advanced HCC patients is urgently required. In this study, we investigated the role of protein phosphatase 2A-B55δ subunit (PP2A-B55δ, encoded by the PPP2R2D gene) and related mechanisms affecting chemotherapy sensitivity of HCC.MethodsExperimental approaches for measuring the levels of PPP2R2D mRNA and B55δ protein in HCC included bioinformatics analyses, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB), immunofluorescence and immunohistochemistry assays. Cell cycle, migration, colony formation, apoptosis, and cell proliferation assays in stable PPP2R2D-knockdown and -overexpression cell lines in vitro, and tumorigenicity assays in vivo, were performed to explore the function of B55δ in cisplatin (cDDP) chemotherapy of HCC. Bioinformatics prediction, luciferase reporter assays, qRT-PCR, WB, and cell cycle analyses were used to reveal the regulatory relationship between microRNA-133b (miR-133b) and PPP2R2D expression. miR-133b mimic and inhibitor were used to elucidate the regulatory mechanism.ResultsOur studies showed that PPP2R2D expression was down-regulated in both HCC tumors and HCC cell lines. Treatment with cDDP increased the amount of B55δ protein. Artificially increasing the expression of B55δ counteracted cyclin-dependent kinase 1 activation, modulated transitions of the cell cycle, and increased the suppressive effect of cDDP on cell migration, colony formation, apoptosis, and proliferation in vitro and tumor growth in vivo, thus enhancing therapeutic efficiency. In contrast, knockdown of B55δ partially inhibited the effect of cDDP chemotherapy. miR-133b was shown to regulate PPP2R2D expression by binding to the 3’-untranslated region of PPP2R2D mRNA. The miR-133b/PPP2R2D signaling pathway affects the effectiveness of cDDP chemotherapy.ConclusionsPP2A-B55δ, regulated by miR-133b, enhances the sensitivity of HCC to cDDP chemotherapy. Our data indicate that PP2A-B55δ might be a novel and attractive target for increasing chemotherapy sensitivity of HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0341-z) contains supplementary material, which is available to authorized users.

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