PMID- 24333213 OWN - NLM STAT- MEDLINE DCOM- 20141007 LR - 20211203 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 723 DP - 2014 Jan 15 TI - Cucurbitacin B inhibits the translational expression of hypoxia-inducible factor-1alpha. PG - 46-54 LID - S0014-2999(13)00922-9 [pii] LID - 10.1016/j.ejphar.2013.12.005 [doi] AB - 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-1alpha protein dose-dependently, whereas it did not affect the expressions of HIF-1beta. Further analysis revealed that cucurbitacin B inhibited HIF-1alpha protein synthesis, without affecting the expression level of HIF-1alpha mRNA or degradation of HIF-1alpha protein. Rather, we found that suppression of HIF-1alpha 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-1alpha 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-1alpha 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. CI - (c) 2013 Published by Elsevier B.V. FAU - Ma, Juan AU - Ma J AD - 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. FAU - Zi Jiang, Ying AU - Zi Jiang Y AD - Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China. FAU - Shi, Hui AU - Shi H AD - Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China. FAU - Mi, Chunliu AU - Mi C AD - Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China. FAU - Li, Jing AU - Li J AD - Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China. FAU - Xing Nan, Ji AU - Xing Nan J AD - Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China. FAU - Wu, Xue AU - Wu X AD - Chemical Biology Research Center, Department of Chemistry, Yanbian University, Yanji 133002, Jilin Province, China. FAU - Joon Lee, Jung AU - Joon Lee J AD - Molecular Cancer Research Center, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: jjlee0908@gmail.com. FAU - Jin, Xuejun AU - Jin X AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20131212 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (HIF1A protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (RNA, Messenger) RN - 0 (Triterpenes) RN - 0 (VEGFA protein, human) RN - 0 (Vascular Endothelial Growth Factor A) RN - 0115W5MABF (cucurbitacin B) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Antineoplastic Agents, Phytogenic/*pharmacology/therapeutic use MH - Cell Line, Tumor MH - Female MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/genetics/metabolism MH - MAP Kinase Signaling System/drug effects MH - Mice MH - Mice, Nude MH - Neoplasm Invasiveness MH - Neoplasms/drug therapy/*metabolism/pathology MH - RNA, Messenger/metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Triterpenes/*pharmacology/therapeutic use MH - Tumor Burden/drug effects MH - Vascular Endothelial Growth Factor A/metabolism MH - Xenograft Model Antitumor Assays OTO - NOTNLM OT - Antitumor activity OT - Cucurbitacin B OT - HIF-1alpha OT - Translation OT - mTOR EDAT- 2013/12/18 06:00 MHDA- 2014/10/08 06:00 CRDT- 2013/12/17 06:00 PHST- 2013/07/22 00:00 [received] PHST- 2013/12/02 00:00 [revised] PHST- 2013/12/04 00:00 [accepted] PHST- 2013/12/17 06:00 [entrez] PHST- 2013/12/18 06:00 [pubmed] PHST- 2014/10/08 06:00 [medline] AID - S0014-2999(13)00922-9 [pii] AID - 10.1016/j.ejphar.2013.12.005 [doi] PST - ppublish SO - Eur J Pharmacol. 2014 Jan 15;723:46-54. doi: 10.1016/j.ejphar.2013.12.005. Epub 2013 Dec 12.