Downregulation of mitochondrial cyclooxygenase-2 inhibits the stemness of nasopharyngeal carcinoma by decreasing the activity of dynamin-related-protein 1

Autor: Wen-Hua Ling, Yuchun Lin, Chengyong He, Huan Yao, Shengwei Jiang, Tengjian Zhou, Zhongning Lin, Peiyu Han, Qun-Ying Zhuang, Shili Zhang, Yi-Jun Huang
Rok vydání: 2017
Předmět:
Dynamins
cancer stemness
0301 basic medicine
Cell Survival
mitochondrial quality control
dynamin-related protein 1
Mice
Nude
Medicine (miscellaneous)
Antineoplastic Agents
Apoptosis
Mitochondrion
03 medical and health sciences
DNM1L
Side population
Downregulation and upregulation
mitochondrial cyclooxygenase-2
Cancer stem cell
Cell Line
Tumor
otorhinolaryngologic diseases
medicine
Animals
Humans
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
Mice
Inbred BALB C
Gene knockdown
Nasopharyngeal Carcinoma
Cyclooxygenase 2 Inhibitors
Chemistry
Carcinoma
Nasopharyngeal Neoplasms
medicine.disease
Disease Models
Animal
stomatognathic diseases
Treatment Outcome
030104 developmental biology
Nasopharyngeal carcinoma
Cyclooxygenase 2
Neoplastic Stem Cells
Cancer research
Mitochondrial fission
Research Paper
Zdroj: Theranostics
ISSN: 1838-7640
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: