title: Perillyl alcohol efficiently scavenges activity of cellular ROS and inhibits the translational expression of hypoxia-inducible factor-1α via mTOR/4E-BP1 signaling pathways.
abstract: Perillyl alcohol (POH) is a dietary monoterpene present in a variety of plants with a pure or mixed form, and it is one of the very few natural substances with anticancer activity. However, the mechanism by which POH unleashes its anticancer activity in tumor cells remains unclear. We here demonstrated the effect of POH on hypoxia-inducible factor-1α (HIF-1α) activation. POH showed the potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines and efficient scavenging activity of cellular Reactive oxygen species (ROS) by hypoxia in tumor cells. Further analysis revealed that POH inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Moreover, we found that suppression of HIF-1α accumulation by POH correlated with strong de-phosphorylation of mammalian target of rapamycin (mTOR) and eIF4E binding protein-1 (4E-BP1), and eukaryotic initiation factor 4E (eIF4E). These results showed that POH inhibited HIF-1α protein synthesis through the inhibition of mTOR/4E-BP1 signaling pathways. Furthermore, POH increased the expression of p53, p21, induced cell cycle arrest in the G1 phase as well as decreased cyclin D1, c-Myc, and Skp2 expression. In vivo studies further confirmed the inhibitory effect of POH on the expression of HIF-1α proteins, leading to a decrease growth of HCT116 cells in a xenograft tumor model. There results show that POH is an effective inhibitor of HIF-1 and provide new perspectives in to the mechanism of its anticancer activity.
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Ke Si
authors.initials: KS
authors.lastname: Wang
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Chunliu
authors.initials: C
authors.lastname: Mi
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Lian Xun
authors.initials: LX
authors.lastname: Piao
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Guang Hua
authors.initials: GH
authors.lastname: Xu
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Xuezheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: xjjin@ybu.edu.cn.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018797:Cell Cycle Proteins; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D039821:Monoterpenes / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D016166:Free Radical Scavengers; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D039821:Monoterpenes; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; C032208:perillyl alcohol; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Anticancer; Cell cycle; HIF-1; Perillyl alcohol (POH); mTOR