title: Cucurbitacin B inhibits the translational expression of hypoxia-inducible factor-1α.
abstract: Cucurbitacin B is a triterpenoid compound isolated from Trichosanthes kirilowii Maximowicz, which has been used in oriental medicine for its antitumor activities. However, the mechanisms by which cucurbitacin B inhibits tumor growth are not fully understood. We here demonstrated the effect of cucurbitacin B on hypoxia-inducible factor-1 (HIF-1) activation. Cucurbitacin B showed the potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1β. Further analysis revealed that cucurbitacin B inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Rather, we found that suppression of HIF-1α accumulation by cucurbitacin B correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1) and extracellular signal-regulated kinase-1/2 (ERK1/2), a pathway known to regulate HIF-1α expression at the translational level. Cucurbitacin B also activated Akt, a mechanistic feature exhibited by established mTOR inhibitors in many tumor cells. Furthermore, cucurbitacin B prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. In vivo studies further confirmed the inhibitory effect of cucurbitacin B on the expression of HIF-1α proteins, leading to a decrease growth of HeLa cells in a xenograft tumor model. These results show that cucurbitacin B is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.
authors: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Juan
authors: J
authors: Ma
authors: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Ying
authors: Y
authors: Zi Jiang
authors: Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Hui
authors: H
authors: Shi
authors: Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Chunliu
authors: C
authors: Mi
authors: Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Jing
authors: J
authors: Li
authors: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Ji
authors: J
authors: Xing Nan
authors: Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China.
authors: Xue
authors: X
authors: Wu
authors: Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: jjlee0908@gmail.com.
authors: Jung
authors: J
authors: Joon Lee
authors: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China; Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: xjjin@ybu.edu.cn.
authors: Xuejun
authors: X
authors: Jin
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014315:Triterpenes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C041246:cucurbitacin B; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Antitumor activity; Cucurbitacin B; HIF-1α; Translation; mTOR