title: Inhibiting the cytoplasmic location of HMGB1 reverses cisplatin resistance in human cervical cancer cells.
abstract: Cervical cancer is the fourth most common malignancy in women worldwide, and resistance to chemotherapy drugs is the biggest obstacle in the treatment of cervical cancers. In the present study, the molecular mechanisms underlying cisplatin resistance in human cervical cancer cells were investigated. When human cervical cancer cells were treated with 10 µg/ml of cisplatin for 24 and 48 h, high mobility group box 1 (HMGB1) protein expression levels significantly increased in a time‑dependent manner. Comparisons between cisplatin‑sensitive HeLa cells and cisplatin‑resistant HeLa/DDP cells revealed higher levels of HMGB1 in HeLa/DDP cells than in HeLa cells. Additionally, the half maximal inhibitory concentration (IC50) value for cisplatin in HeLa/DDP cells was 5.3‑fold that in HeLa cells. Analysis of the distribution of cellular components revealed that HMGB1 translocation from the nucleus to cytoplasm contributed to cisplatin resistance. This was further confirmed by demonstration that ethyl pyruvate treatment suppressed the cytoplasmic translocation of HMGB1, resulting in inhibition of HeLa cell proliferation. Furthermore, endogenous HMGB1 was inhibited with HMGB1‑specific short hairpin (sh)RNA, and MTT assay results showed that interference with HMGB1 expression reduced cell viability and potentially reversed cisplatin resistance in HeLa cells. Transfection with HMGB1 shRNA was demonstrated to induce cell apoptosis in HeLa cells, as detected by FACS analysis. In addition, administration of recombinant HMGB1 protein in HeLa cells promoted cell autophagy, mediated by the phosphorylation of extracellular signal‑regulated kinase 1/2. Thus, cytoplasmic HMGB1 translocation and HMGB1‑induced cell autophagy are proposed to contribute to cisplatin resistance by inhibiting apoptosis of cervical cancer cells. HMGB1 could, therefore, represent a novel therapeutic target for, and a diagnostic marker of, chemotherapy resistant cervical cancers.
authors.affiliation: School of Medical Information and Engineering, Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
authors.forename: Jiyi
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Yu
authors.affiliation: Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
authors.forename: Xueqin
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
authors.forename: Xiguang
authors.initials: X
authors.lastname: Mao
authors.affiliation: Department of Obstetrics and Gynecology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P.R. China.
authors.forename: Yujiao
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002584:Cervix Uteri / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D011773:Pyruvates / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D011773:Pyruvates; D034741:RNA, Small Interfering; C046522:ethyl pyruvate; D002945:Cisplatin