Therapeutic Value of PLK1 Knockdown in Combination with Prostate Cancer Drugs in PIM-1 Overexpressing Prostate Cancer Cells
Annual rept. 15 Apr 2012-14 Apr 2013
VANDERBILT UNIV NASHVILLE TN
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Our main goal was to test the therapeutic value of PLK1 knockdown in combination with prostate cancer drugs in Pim-1 overexpressing cells. We hypothesized that depletion of PLK1 will result in synthetic lethality in Pim-1 overexpressing cells. We further hypothesized that depletion of PLK1 will further sensitize Pim-1 overexpressing cells to prostate cancer drugs. Our specific aims were to test whether loss of PLK1 can result in synthetic lethality in Pim-1 overexpressing cells and to test whether the loss of PLK1 can synergistically sensitize Pim-1 overexpressing cells to prostate cancer drugs. To date, we have found that loss of PLK1 reduced cell viability in general and this effect is more severe in Pim1 over expressing cells, suggesting synthetic lethality of Plk1 depletion and Pim-1 over expression.We found that Pim1-overexpressing cells are more prone to mitotic arrest followed by apoptosis. Interestingly, inhibition of PLK1 either by shRNA or BI 2536 in prostate cancer cell lines results in a reduction in MYC protein levels, and an increase in p53 levels. We also found that PLK1 depletion impairs the in vivo tumoriegencity of Pim1-expressing cells. Using Plk1 inhibitor, BI 2536, we confirmed these finding. Furthermore, we also found that PLK1 and PIM1 are frequently co-expressed in human prostate tumors using human tissue microarray samples.
- Medicine and Medical Research