We recently found that Polo-like kinase 2 (Plk2) is a direct target for transcriptional regulation by p53 and Plk2 deficient cells demonstrate increased cell death in response to replication stress. Plk2 was found to bind to cell cycle checkpoint proteins, Chk2, Chk1, Ser 317 Chk1 and p53. Our goals have been to better understand why Plk2 is regulated by the tumor suppressor p53 and to determine what role Plk2 plays in tumor progression. As determined by in vivo imaging, the majority of Plk2 deficient xenograft tumors treated with CPT-11 demonstrate increased uptake of the blood pooling agent, Angiosense 750 at day 16 post-inoculation consistent with the possibility that Plk2 knock-down might promote vascularity in tumors. There were no observed changes in Plk1 and Plk3 expression in these xenograft tumors. H460 human non-small cell lung carcinoma cells with stable knock-down of Plk2 demonstrated increased cell death in response to CPT-11. Tumor xenografts of Plk2 knock-down cells demonstrate that Plk2 deficiency may increase cell proliferation while sensitizing tumors to CPT-11. As compared to empty-vector bearing tumors, Plk2 deficient tumors were larger in size and following CPT-11 treatment demonstrated PARP-cleavage and increased TUNEL staining. Plk2 deficiency clearly sensitizes tumors to cell death after CPT-11 treatment in vivo suggesting that inhibitors of Plk2 maybe useful to develop for cancer therapy.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA