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

Abstract

Cyclin D1 is required for cells to progress from the G1 phase into the S phase of the cell cycle. Several tumors display elevations in cyclin D1, concomitant with increased cell cycle progression and proliferation. QTRRE (rodent) and ACHN (human) cell models of renal cell carcinoma display elevated cyclin D1 protein levels. Pentoxifylline (PTX), a competitive non‐specific phosphodiesterase inhibitor, has found recent use as an adjunct in chemotherapy for patients to help treat cachexia and capillary leak syndrome. We report that PTX causes a time‐ (1–24 hr) and dose‐dependent (35 μM −3.5 mM) decrease in cyclin D1 protein levels in both cell lines. PTX's ability to decrease cyclin D1 in QTRRE and ACHN was abolished in the presence of a proteasome inhibitor (MG‐132, 10μM) as well as a GSK‐3β inhibitor (VI, 1μM). Consistent with decreases in cyclin D1, flow cytometric analysis revealed that QTRRE and ACHN cells treated for 24hr with PTX undergo enhanced cell cycle arrest in the G1 phase (170 & 140%, respectively). Collectively the data suggest that PTX decreases cyclin D1 protein 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)