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Lovastatin Induction of Cyclin-dependent Kinase Inhibitors in Human Breast Cells Occurs in a Cell Cycle-independent Fashion¹

Division of Molecular Medicine, Laboratory of Diagnostic Oncology, Wadsworth Center, Albany, New York 12201

Cyclin-dependent kinase inhibitors (CKIs) p21, p27, p16, and p15 are an essential and integral part of cell cycle regulation. Studies on the expression of these inhibitors in normal versus tumor human breast cancer cells revealed that although p27 and p16 are expressed at higher levels in tumor cells, p21 and p15 expression were higher in normal cells. Analysis on the expression pattern of these proteins throughout the cell cycle in synchronized cells demonstrated a substantial increase in p21 during the S-phase in normal cells and barely detectable expression of p21 in any phase of the tumor cell cycle. Levels of p15, p16, and p27 remained relatively constant throughout the cell cycle of normal and tumor cells. Synchronization of tumor cells by lovastatin, which arrests cells in G₁, resulted in increased levels of p21 and p27 with a concomitant decrease in cyclin-dependent kinase 2-associated kinase activity. Synchronization of cells by double-thymidine block did not result in the induction of p21 or p27. These observations suggest that lovastatin causes a profound cell cycle-independent alteration of CKI expression which is distinct from growth factor deprivation or thymidine block.

¹ This research was supported in part by Grant DAMD-17-94-J-4081, AIBS 1579 from the U.S. Army Medical Research Acquisition Activity and by Grant No. R29CA66062 from the National Cancer Institute (both to K. K.).

² To whom requests for reprints should be addressed, at Wadsworth Center, Empire State Plaza, P.O. Box 509, Albany, NY 12201. Phone: (518) 486-5799; Fax: (518) 486-5798; E-mail: keyomars@wadsworth.org.

Received 10/24/96. Accepted 1/ 3/97.

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