Stathmin, a microtubule-destabilizing
phosphoprotein, is highly expressed in
ovarian cancer, but the pathophysiological significance of this
protein in ovarian
carcinoma cells remains poorly understood. This study reports the involvement of
stathmin in the mTOR/HIF-1 α /
VEGF pathway in ovarian
clear cell adenocarcinoma (CCA) during
hypoxia. HIF-1 α
protein and
VEGF mRNA levels were markedly elevated in RMG-1 cells, a CCA cell line, cultured under hypoxic conditions.
Rapamycin, an inhibitor of mTOR complex 1, reduced the level of HIF-1 α and blocked phosphorylation of
ribosomal protein S6 kinase 1 (S6K), a transcriptional regulator of mTOR, demonstrating that
hypoxia activates mTOR/S6K/HIF-1 α signaling in CCA. Furthermore,
stathmin knockdown inhibited
hypoxia-induced HIF-1 α and
VEGF expression and S6K phosphorylation. The silencing of
stathmin expression also reduced Akt phosphorylation, a critical event in the mTOR/HIF-1 α /
VEGF signaling pathway. By contrast,
stathmin overexpression upregulated
hypoxia-induced HIF-1 α and
VEGF expression in OVCAR-3 cells, another CCA cell line. In addition, suppression of Akt activation by
wortmannin, a
phosphoinositide 3-kinase (PI3K) inhibitor, decreased HIF-1 α and
VEGF expression. These results illustrate that regulation of HIF-1 α through the PI3K/Akt/mTOR pathway is controlled by
stathmin in CCA. Our findings point to a new mechanism of
stathmin regulation during
ovarian cancer.