title: Hypoxia promotes glycogen synthesis and accumulation in human ovarian             clear cell carcinoma.
abstract: Ovarian clear cell carcinoma (OCCC) has several significant characteristics             based on molecular features that are distinct from those of ovarian high-grade             serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature             of OCCC and in the present study its metabolic mechanism was investigated. The             amount of glycogen in cells cultured under hypoxia increased significantly and             approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions.             Periodic acid-Schiff positive staining also demonstrated intracellular glycogen             storage. Western blot analysis revealed that HIF1α, which was overexpressed and             stabilized under hypoxic conditions, led to an increase in the levels of cellular             glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive             phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in             both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme             activity, and glycogen synthase kinase 3 beta (GSK3β) phosphorylated at Ser9,             which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme             activity. By contrast, the level of PYGM-b decreased. These results indicated             that the glycogen accumulation under a hypoxic environment resulted in the promotion             of glycogen synthesis, but did not lead to inhibition of glycogen degradation             and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of             the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic             subunit p110α of PI3K. The resulting activation of AKT (phosphoSer473) also plays             a role as a central enhancer in glycogen synthesis through suppression of GSK3β             via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin             and doxorubicin to various degrees. In conclusion, the hypoxic conditions together             with HIF1 expression and stabilization increased the intracellular glycogen contents             and resistance to the anticancer drugs.
authors.affiliation: Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan. surf-side@hotmail.co.jp
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Iida
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Aoki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Asakura
authors.forename: Kazu
authors.initials: K
authors.lastname: Ueda
authors.forename: Nozomu
authors.initials: N
authors.lastname: Yanaihara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takakura
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Yamada
authors.forename: Aikou
authors.initials: A
authors.lastname: Okamoto
authors.forename: Tadao
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ohkawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D002277:Carcinoma / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004317:Doxorubicin / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D006003:Glycogen / Q000096:biosynthesis*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D006003:Glycogen; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D002945:Cisplatin