Pentoxifylline induces GSK‐3β‐independent proteasomal degradation of cyclin D1 and arrests renal cancer cells in the G1 phase (616.5)

Cyclin D1 is required for progression from G1 into S phase of the cell cycle. Over‐expression of cyclin D1 causes an increase in cell cycle progression and proliferation. Canonical cyclin D1 degradation is initiated by phosphorylation of Thr286 by GSK‐3β. QTRRE (rodent) and ACHN (human) renal cell carcinoma (RCC) cell lines exhibit elevated levels of cyclin D1. Pentoxifylline (PTX) is used as an adjunct in chemotherapy to treat cachexia. We report that PTX causes a time‐ and dose‐dependent decrease in cyclin D1 levels and G1 cell cycle arrest in QTRRE and ACHN cells. RT‐PCR analysis showed no significant changes in cyclin D1 mRNA. However, PTX’s ability to decrease cyclin D1 was prevented by the proteasome inhibitor, MG‐132. Inhibition of GSK‐3β with LiCl in the presence of PTX failed to rescue cyclin D1 levels. PTX increased pSer9 on GSK‐3β, indicative of an inhibition of GSK‐3β activity. Following siRNA knockdown of GSK‐3β, PTX retained the ability to decrease cyclin D1 levels. Moreover, PTX treatment in the presence of MG‐132 revealed no increase in pThr286 compared to control. Our data indicate that PTX initiates GSK‐3β‐independent proteasomal degradation of cyclin D1 and arrests the RCC cells in the G1 phase. Because our findings demonstrate a novel anti‐cancer property of PTX, its use as an adjuvant therapy in RCC treatment should be further explored. Grant Funding Source : Supported by ES006694, AstraZeneca Studentship, T32ES016652