PENTOXIFYLLINE INITIATES GSK-3Β-INDUCED PROTEASOMAL DEGRADATION OF CYCLIN D1 AND ARRESTS RENAL CANCER CELLS IN THE G1 PHASE

picture of Wesley Cai presenting his/her poster: PENTOXIFYLLINE INITIATES GSK-3Β-INDUCED PROTEASOMAL DEGRADATION OF CYCLIN D1 AND ARRESTS RENAL CANCER CELLS IN THE G1 PHASE

Wesley Cai , Nicholas J. Mastrandrea, Kim Y. Tham, Terrence J. Monks, Serrine S. Lau

PENTOXIFYLLINE INITIATES GSK-3Β-INDUCED PROTEASOMAL DEGRADATION OF CYCLIN D1 AND ARRESTS RENAL CANCER CELLS IN THE G1 PHASE

Cyclin D1 is required for cells to progress from G­1 to S phase of the cell cycle, and mutation or over-expression of cyclin D1 leads to uncontrolled proliferation. Cyclin D1 over-expression is therefore implicated in a variety of cancers. QTRRE (rat) and ACHN (human) renal cancer cells possess elevated levels of cyclin D1. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor and an FDA approved drug, induces a time- (0-24 hr) and dose- (35 µM-3.5 mM) dependent decrease in cyclin D1 levels in both cell models. QTRRE and ACHN cells treated with PTX (24 hr) undergo enhanced cell cycle arrest in the G1 phase (170 & 140%, respectively). While RT-PCR showed no change in cyclin D1 transcription after PTX treatment (0-24hr), a decrease of cyclin D1 t1/2 was observed, suggesting an increase in protein degradation. Furthermore, PTX-induced decrease of cyclin D1 was abolished in the presence of a proteasome inhibitor (MG-132, 10µM) as well as GSK-3β inhibitors (LiCl, 20mM and VI, 10uM). MS proteomics analysis following cyclin D1 antibody pull-down revealed that cyclin D1 associates with proteasomal subunit α type 5 and polyubiquitins B & C. The data suggest that PTX decreases cyclin D1 levels by stimulating GSK-3β-induced proteasomal degradation, which promotes G1 phase cell cycle arrest. Moreover, because our findings reveal a novel anti-cancer chemotherapeutic property of PTX, the utility of PTX as an adjuvant therapy in the treatment of cancer should be further explored. (AstraZeneca Studentship, T32ES016652, P30ES006694)

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