title: Succinate dehydrogenase subunit B inhibits the AMPK-HIF-1α pathway in human ovarian cancer in vitro.
abstract: BACKGROUND
  Ovarian carcinoma is one of the most common gynecological cancers with high mortality rates. Numerous evidences demonstrate that cancer cells undergo metabolic abnormality during tumorigenesis in tumor microenvironment and further facilitate tumor progression. Succinate dehydrogenase (SDH or Complex II) is one of the important enzymes in the tricarboxylic acid (TCA) cycle. Succinate dehydrogenase subunit B (SDHB) gene, which encodes one of the four subunits of SDH, has been recognized as a tumor suppressor. However the role of SDHB in ovarian cancer is still unclear.
  
  
  METHODS
  Using the SDHB specific siRNA and overexpression plasmid, the expression of SDHB was silenced and conversely induced in ovarian cancer cell lines SKOV3 and A2780, respectively. The possible role of SDHB in ovarian cancer was investigated in vitro, using proliferation, migration and invasion assays. To explore the mechanism, proliferation and migration related proteins such as Bcl-2, cleaved caspase 3, p-ERK, MMP-2, and p-FAK were examined by western blot. P-P38, p-AMPKα, and HIF-1α were also examined by western blot. CoCl2 was used to induce HIF-1α expression in SKOV3 and A2780 cells.
  
  
  RESULTS
  SDHB silencing promoted cell proliferation, invasion, and migration, but inhibited apoptosis of SKOV3 and A2780 cells. In contrast, overexpression of SDHB inhibited cell proliferation, invasion, migration, and promoted apoptosis in SKOV3 cells. It was observed that up-regulation of Bcl-2 and MMP-2, activation of p-P38, p-ERK, and p-FAK, inhibition of cleaved caspase 3 in SDHB-silenced cells. Meanwhile, decreased Bcl-2 and MMP-2, inhibition of p-P38, p-ERK, and p-FAK, activation of cleaved caspase 3 were shown in SDHB-overexpressed SKOV3 cells. HIF-1α, an essential factor in tumor progression, was up-regulated in SDHB-silenced cells with the activation of p-AMPKα and down-regulated in SDHB-overexpressed cancer cells with the decreased p-AMPKα. And SDHB was proved to be decreased due to upregulation of HIF-1α expression in CoCl2-treated cancer cells.
  
  
  CONCLUSIONS
  Our results firstly revealed that SDHB played a key role in cell proliferation, invasion, migration, and apoptosis of human ovarian carcinoma via AMPK-HIF-1α pathway. SDHB-overexpression might be a new approach to inhibit tumor progression in human ovarian carcinoma.
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. chenlilangood@163.com.|Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China. chenlilangood@163.com.
authors.forename: Lilan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. ting_mail@126.com.|Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China. ting_mail@126.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. drzhangshu@hotmail.com.|Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China. drzhangshu@hotmail.com.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. jsjhzh@126.com.|Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China. jsjhzh@126.com.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. hrbmu.ok@163.com.|Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China. hrbmu.ok@163.com.
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, P. R. China. diwen163@163.com.|Shanghai Key Laboratory of Gynecologic Oncology, Shanghai, 200127, P. R. China. diwen163@163.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Di
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013385:Succinate Dehydrogenase / Q000502:physiology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D000255:Adenosine Triphosphate; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D000263:Adenylate Kinase