Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma

Abstract

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.

Overexpression of GYS1, MIF, and MYC Is Associated With Adverse Outcome and Poor Response to Azacitidine in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…Its relation with solid cancer has already been described. 33 In contrast, there is no information on the role of GYS1 expression in the physiopathology or prognostic effect in hematological malignancies, however, there is a large amount of evidence on the involvement of MYC and VEGF on the biology and outcome of myeloid neoplasms. 34,35 In addition, new therapeutic strategies are being developed, targeting some of these pathways, such as the use of anti-VEGF, alone or in combination with standard chemotherapy, although results are still disappointing.…”

HDAC6 regulates sensitivity to cell death in response to stress and post-stress recovery

“…HIF-1α is one of the best-described regulatory gene and transcription factors that are activated under hypoxia, and it plays an important role in the activation of resistance mechanisms to anticancer drugs (Iida et al 2012). It has been shown that HDAC6 and HDAC4 interact with HIF-1α directly to control the acetylation level and degradation of HIF-1α in a VHLindependent manner (VPA and LAQ824) (Qian et al 2006).…”

Glycogen: A must have storage to survive stressful emergencies

“…[53][54][55] In analogy with the important role of glycogen in survival to stress, glycogen could also be an important molecule that fuels tumorigenesis. Glycogen accumulates in many cancer types including ovarian cancer, 56 kidney cancer, 57 colorectal cancer, 58 bladder cancer, 59 and others. 60 In addition, higher glycogen levels were detected in breast, kidney, bladder, uterus, skin, ovary, and brain cancer cell lines 60 , and recent studies have demonstrated a critical role for glycogen in the survival of cancer cells to hypoxic environments and glucose restriction.…”