Hypoxia-inducible factor-1alpha blocks differentiation of malignant gliomas.
Aberrant differentiation is a characteristic feature of neoplastic transformation, while hypoxia in solid tumors is believed to be linked to aggressive behavior and poor prognosis. However, the possible relationship between hypoxia and differentiation in malignancies remains poorly defined. Here we show that rat C6 and primary human malignant glioma cells can be induced to differentiate into astrocytes by the well-known adenylate cyclase activator forskolin. However, hypoxia-inducible factor-1alpha expression stimulated by the hypoxia mimetics cobalt chloride or deferoxamine blocks this differentiation and this effectiveness is reversible upon withdrawal of the hypoxia mimetics. Importantly, knockdown of hypoxia inducible factor-1alpha by RNA interference restores the differentiation capabilities of the cells, even in the presence of cobalt chloride, whereas stabilization of hypoxia-inducible factor-1alpha through retarded ubiquitination by von Hippel-Lindau tumor suppressor gene silence abrogates the induced differentiation. Moreover, targeting of HIF-1 using chetomin, a disrupter of HIF-1 binding to its transcriptional co-activator CREB-binding protein (CBP)/p300, abolishes the differentiation-inhibitory effect of hypoxia-inducible factor-1alpha. Administration of chetomin in combination with forskolin significantly suppresses malignant glioma growth in an in vivo xenograft model. Analysis of 95 human glioma tissues revealed an increase of hypoxia-inducible factor-1alpha protein expression with progressing tumor grade. Taken together, these findings suggest a key signal transduction pathway involving hypoxia-inducible factor-1alpha that contributes to a differentiation defect in malignant gliomas and sheds new light on the differentiation therapy of solid tumors by targeting hypoxia-inducible factor-1alpha.
Lu
Huimin
H
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
Li
Yan
Y
Shu
Minfeng
M
Tang
Jianjun
J
Huang
Yijun
Y
Zhou
Yuxi
Y
Liang
Yingjie
Y
Yan
Guangmei
G
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D003035:Cobalt / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D026121:Indole Alkaloids / Q000494:pharmacology; D008297:Male; D051379:Mice; D051381:Rats; D014407:Tumor Cells, Cultured
D004220:Disulfides; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026121:Indole Alkaloids; C001598:chetomin; D005576:Colforsin; D003035:Cobalt; C018021:cobaltous chloride; D003676:Deferoxamine