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Hormel Institute, University of Minnesota, Austin, Minnesota

Requests for reprints: Junxuan Lü, Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: 507-437-9680; Fax: 507 437-9606. E-mail: jlu{at}hi.umn.edu

The issue of p53 requirement for the caspase-mediated apoptosis induced by selenium in a cancer chemoprevention or chemotherapy context has not been critically addressed. We and others have shown that selenite induces apoptotic DNA laddering in the p53-mutant DU145 prostate cancer cells and the p53-null HL60 leukemia cells without the cleavage of poly(ADP-ribose) polymerase (PARP; i.e., caspase-independent apoptosis), whereas selenium compounds leading to the formation of methylselenol induce caspase-mediated apoptosis in these cells. Because selenite induces DNA single strand breaks, and because certain types of DNA damage activate p53, we investigated whether the human LNCaP prostate cancer cells, which contain a wild-type p53, execute selenite-induced apoptosis through caspase pathways. The results showed that exposure of LNCaP cells for 24 hours to lower micromolar concentrations of selenite led to DNA laddering, and to the cleavage of PARP and several pro-caspases. In contrast to this apoptosis sensitivity, LNCaP cells were rather resistant to similar concentrations of the methylselenol precursor methylseleninic acid. Selenite treatment led to a significant increase in p53 phosphorylation on Ser-15 (Ser¹⁵P). Time course experiments showed that p53 Ser¹⁵P occurred several hours before caspase activation and PARP cleavage. The general caspase inhibitor zVADfmk completely blocked PARP cleavage, and significantly decreased DNA laddering, but did not affect p53 Ser¹⁵P. An inhibitor for caspase-8 was equally as protective as that for caspase-9 against the selenite-induced apoptosis. Attenuating p53 by a chemical inhibitor pifithrin- decreased the selenite-induced p53 Ser¹⁵P and led to concordant reductions of PARP cleavage and apoptosis. In summary, selenite-induced p53 Ser¹⁵P appeared to be important for activating the caspase-mediated apoptosis involving both the caspase-8 and the caspase-9 pathways in the LNCaP cells.

Key Words: selenium • selenite • methylseleninic acid • caspases • apoptosis • p53 phosphorylation • prostate cancer

Grant support: The Hormel Foundation and grants from the Department of Defense Prostate Cancer Program (DAMD17-02-0007) and National Cancer Institute (CA92231).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address of Z. Wang: Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado. The University of Minnesota is an equal opportunity educator and employer.

Received 3/16/04; revised 4/28/04; accepted 5/11/04.