Journal
THERANOSTICS
Volume 7, Issue 5, Pages 1389-1406Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.17647
Keywords
mitochondrial cyclooxygenase-2; nasopharyngeal carcinoma; cancer stemness; dynamin-related protein 1; mitochondrial quality control
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Funding
- National Natural Science Foundation of China (NSFC) [81472997, 81573181, 81402648]
- Natural Science Foundation of Fujian Province of China [2014J01372, 2015J01344]
- Xiamen Municipal Bureau of Ocean and Fisheries [14PYY051SF04]
- Early-stage Project of National Key Basic Research Program of China [2014CB560710]
- NSFC [81130052]
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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.
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