5347

PLK1

polo-like kinase 1;PLK1;polo-like kinase 1

PLK-1|cell cycle regulated protein kinase|polo (Drosophia)-like kinase|polo like kinase|serine/threonine-protein kinase 13|serine/threonine-protein kinase PLK1

16p12.2

protein-coding

OBJECTIVES: Polo-like kinase 1 (Plk1) has been widely pursued as an oncology target because it is overexpressed in several human tumor types. To investigate whether Plk1 plays a general role in bladder urothelial carcinoma, we examined the expression of Plk1 protein in bladder urothelial carcinoma and cell lines, and analyzed the relationship among Plk1 protein expression, metastasis, and recurrence of urinary bladder urothelial carcinoma. METHODS: Immunohistochemistry was used to detect the expression of Plk1 in 120 bladder urothelial carcinoma. Moreover, the expression of Plk1 was analyzed by Western blot in 60 bladder urothelial carcinoma and 21 normal epithelial tissues. MTT assay and flow cytometry and transwell assay were used to examine the proliferative and invasive ability of bladder cancer cells with the treatment of scytonemin (the inhibitor of Plk1). Statistical analysis was used to discuss the association between Plk1 expression and clinicopathologic parameters, tumor metastasis and recurrence, and the proliferative and invasive ability and cell cycle process of the bladder cancer cells. RESULTS: There was a significantly higher Plk1expressions in bladder urothelial carcinoma and highly invasive bladder T24 cells than those in bladder normal tissues and the superficial bladder BIU-87 cells. Plk1 expression was positively correlated with histologic grade, pT stage, recurrence, and metastasis. With the increasing concentration of scytonemin, we found that not only the cell proliferation and invasion activity decreased significantly, but also the cell cycle was blocked at G2/M stage. CONCLUSION: Plk1 expression status was closely correlated with important histopathologic characteristics (grades and stages) and the recurrence and metastasis of bladder urothelial carcinomas. Furthermore, Plk1 played an important function on the bladder cancer cells' proliferation by regulating the cancer cell cycle from G1/S to G2/M and probably promoted the invasion and metastasis of bladder cancer.

Few therapeutic strategies exist for the treatment of metastatic tumor cells in the brain because the blood-brain barrier (BBB) limits drug access. Thus the identification of molecular targets and accompanying BBB permeable drugs will significantly benefit brain metastasis patients. Polo-like kinase 1 (Plk1) is an attractive molecular target because it is only expressed in dividing cells and its expression is upregulated in many tumors. Analysis of a publicly available database of human breast cancer metastases revealed Plk1 mRNA expression was significantly increased in brain metastases compared to systemic metastases (P = 0.0018). The selective Plk1 inhibitor, GSK461364A, showed substantial uptake in normal rodent brain. Using a breast cancer brain metastatic xenograft model (231-BR), we tested the efficacy of GSK461364A to prevent brain metastatic colonization. When treatment was started 3 days post-injection, GSK461364A at 50 mg/kg inhibited the development of large brain metastases 62% (P = 0.0001) and prolonged survival by 17%. GSK461364A sensitized tumor cells to radiation induced cell death in vitro. Previously, it was reported that mutations in p53 might render tumor cells more sensitive to Plk1 inhibition; however, p53 mutations are uncommon in breast cancer. In a cohort of 41 primary breast tumors and matched brain metastases, p53 immunostaining was increased in 61% of metastases; 44% of which were associated with primary tumors with low p53. The data suggest that p53 overexpression occurs frequently in brain metastases and may facilitate sensitivity to Plk1 inhibition. These data indicate Plk1 may be a new druggable target for the prevention of breast cancer brain metastases.