Perillyl alcohol causes G1 arrest through p15INK4b and p21WAF1/Cip1 induction

Koyama,Makoto; Sowa,Yoshihiro; Hitomi,Toshiaki; Iizumi,Yosuke; Watanabe,Motoki; Taniguchi,Tomoyuki; Ichikawa,Masami; Sakai,Toshiyuki

doi:10.3892/or.2012.2167

Perillyl alcohol causes G1 arrest through p15INK4b and p21WAF1/Cip1 induction

Authors:
- Makoto Koyama
- Yoshihiro Sowa
- Toshiaki Hitomi
- Yosuke Iizumi
- Motoki Watanabe
- Tomoyuki Taniguchi
- Masami Ichikawa
- Toshiyuki Sakai
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Affiliations: Department of Molecular-Targeting Cancer Prevention, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
Published online on: December 6, 2012 https://doi.org/10.3892/or.2012.2167
Pages: 779-784

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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 p15INK4b and p21WAF1/Cip1, resulting in hypophosphorylation of the retinoblastoma (RB) protein and subsequent G1 arrest in human immortalized keratinocyte HaCaT cells. The induction of p15INK4b was mediated through its promoter, but that of p21WAF1/Cip1 was not. The small interfering RNA (siRNA) of either p15INK4b or p21WAF1/Cip1 significantly attenuated the increase in the G1 cell population caused by POH. The induction of p15INK4b and p21WAF1/Cip1 and subsequent G1 arrest by POH was also observed in other cancer cell lines. These results suggest that the induction of p15INK4b as well as p21WAF1/Cip1 is associated with the antiproliferative effect of POH.

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