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Dan Ma,1 Yong Huang,2 Shurong Song11Department of Obstetrics and Gynecology, Tianjin Third Central Hospital, Tianjin 300170, People’s Republic of China; 2Department of Dermatology, Tianjin Gongan Hospital, Tianjin 300042, People’s Republic of ChinaCorrespondence: Shurong SongDepartment of Obstetrics and Gynecology, Tianjin Third Central Hospital, 83 Jingtang Road, Hedong District, Tianjin 300170, People’s Republic of ChinaTel +86 22 8411 2232Email srsongtjtch@outlook.comBackground: Human papillomavirus (HPV), the major cause of cervical cancer worldwide, is associated with infection of HPV (Oncogenic HPV). Cancer patients who develop drug resistance are resulted in failure of chemotherapy.Objective: We investigated the mechanisms for the HPV E6/E7 oncoprotein-mediated 5-fluorouracil (5-Fu) sensitivity.Methods: HPV-16 E6/E7 was transfected into human cervical cancer cell lines. Glycolysis rate was assessed. Xenograft model was established to examine the in vivo therapeutic effects of E6/E7 inhibition and 5-Fu treatments.Results: The HPV-16 E6/E7 oncoprotein induces 5-Fu resistance in cervical cancer cells. Overexpression of E6/E7 renders CaSki and SiHa cells resistant to 5-Fu treatments. We found E6/E7 expressions were significantly upregulated in 5-Fu-resistant cells compared with parental cells. Moreover, the cellular glycolysis rate was significantly increased in 5-Fu-resistant cells. The glucose uptake, lactate production, and expressions of glycolysis enzymes were upregulated in 5-Fu-resistant cells. We report the E6/E7-mediated 5-Fu resistance was through upregulation of glycolysis pathway. Importantly, inhibition of E6/E7 by shRNA effectively decreased cellular glycolysis and overcame 5-Fu resistance using in vitro and in vivo xenograft model.Conclusion: Our study contributed to understanding the molecular mechanisms for HPV E6/E7-mediated 5-Fu resistance and development of new therapeutic strategies against cervical cancer.Keywords: human papillomavirus, Warburg effect, chemoresistance, 5-Fu, cervical cancer, HPV E6/E7 |
