PARENT SESSION
1:30 PM to 3:30 PM
Tuesday, April 23, 2002
Poster Session 24 Signal Transduction
Room: Nevada Exhibition Center
(P29-282) TPA radiosensitizes prostate cancer cells by down-regulation of ATM .
Truman, J. P.1, Liao, W-C.1, Kolesnick, R.1, Lavin, M.2, Fuks, Z.1, Leibel, S.1, Haimovitz-Friedman, A.*,1, 1 Memorial Sloan-Kettering Cancer Center, New York, NY2 The Queensland Cancer Fund Research Laboratory, Brisbane, Australia
ABSTRACT-
Functional loss of the Ataxia Telangiectasia-Mutated (ATM) gene product leads to a pleiotropic phenotype, with radiation hypersensitivity as one of the most widely studied event. We reported recently that treatment of LNCaP human prostate cancer cells with the Protein Kinase C activator 12-O-tetradecanoylphorbol 12-acetate (TPA) and radiation initiated an apoptotic response via activation of the enzyme ceramide synthase (CS) and de novo synthesis of the sphingolipid ceramide (Garzotto M et. al. 1999), while radiation alone failed to induce apoptosis in LNCaP cells. Recent studies in our laboratory showed that the CS pathway is activated in response to DNA damage and that this activation is regulated by the ATM gene product (Liao W-C et. al. 1999). Here, we show that TPA reduces the ATM protein level in both LNCaP and CWR22-RV1, but did not affect ATM levels in other cell lines tested. Radiation alone had no significant effect on ATM levels and when applied together with TPA induced no further ATM reduction. TPA-induced reduction of ATM protein correlated with increased apoptosis in these cell lines. Quantitative RT-PCR showed a 50% reduction of ATM mRNA between 8-16 h of TPA treatment. Gel-shift analysis showed a significant reduction in the amount of Sp-1 transcription factor binding to ATM promoter, as early as 4 h post TPA treatment for LNCaP, but with slower kinetics for CWR22-RV1. These data demonstrate that in human prostate cell lines, transcription of ATM can be attenuated by TPA treatment, enhancing sensitivity to ionizing radiation. This investigation defines a new approach to overcome radiation resistance in human prostate cancer cells in a cell-type specific manner.
KEYWORDS: radiosensitizer, prostate cancer, ATM, ceramide