title: Perillyl alcohol causes G1 arrest through p15(INK4b) and p21(WAF1/Cip1) induction.
abstract: The monoterpene perillyl alcohol (POH) is a naturally occurring compound derived from citrus fruits, mint and herbs. It exhibited chemotherapeutic potential against various malignant tumors in preclinical models and is currently being tested in clinical trials in patients with refractory advanced cancers. POH inhibits cellular proliferation at the G1 phase of the cell cycle in vitro. However, the molecular mechanisms responsible for this effect have not been sufficiently elucidated. Here we showed that 1.0 mM POH upregulates p15(INK4b) and p21(WAF1/Cip1), resulting in hypophosphorylation of the retinoblastoma (RB) protein and subsequent G1 arrest in human immortalized keratinocyte HaCaT cells. The induction of p15(INK4b) was mediated through its promoter, but that of p21(WAF1/Cip1) was not. The small interfering RNA (siRNA) of either p15(INK4b) or p21(WAF1/Cip1) significantly attenuated the increase in the G1 cell population caused by POH. The induction of p15(INK4b) and p21(WAF1/Cip1) and sub-sequent G1 arrest by POH was also observed in other cancer cell lines. These results suggest that the induction of p15(INK4b) as well as p21(WAF1/Cip1) is associated with the antiproliferative effect of POH.
authors.affiliation: Department of Molecular-Targeting Cancer Prevention, Graduate                     School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji,                     Kamigyo-ku, Kyoto 602-8566, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Koyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hitomi
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Iizumi
authors.forename: Motoki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Masami
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes; D039821:Monoterpenes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D039821:Monoterpenes; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; C032208:perillyl alcohol