Abstract 1766: Effects of lovastatin on the PRL-3 cascade of events in prostate cancer
Authors: Palmer Allison K. , Munirathinam Gnanasekar 
Published: August 2015

Phosphatase of Regenerating Liver 3 (PRL-3) has recently been demonstrated to play a role in the cellular processes associated with cancer metastasis and has been suggested as a potential new target for cancer therapies. Several pre-clinical evaluations targeting PRL-3 have shown great promise for cancer treatment. Statins are a class of drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and have been shown to have anti-cancer properties in a variety of cancer types including prostate cancer (PC); previous work has shown that one of the anti-cancer effects of statins is the inhibition of protein prenylation, a post translational modification that allows proteins to associate with the plasma membrane. Prenylation of PRL-3 plays a critical role in cell membrane localization and metastatic process; therefore, targeting PLR-3 prenlyation may be an attractive strategy. In our recent work, we have identified that PRL-3 is highly expressed in aggressive prostate cancer cells and is critical for the motility behavior. Our hypothesis is that lovastatin treatment will reduce the metastatic properties of PC cells by inhibiting prenylation of PRL-3 and therefore reduce the oncogenic effects of the PRL-3 cascade of events required for PC metastasis.

Advanced PC cell line, DU145 was used in this study to characterize PRL-3 function. Cell viability assays showed that lovastatin has dose dependent effects on DU145. Western Blot analysis was then used to analyze expression levels of PRL-3 and its downstream proteins in DU145 cells treated with lovastatin. Cellular localization of PRL-3 following lovastatin treatments was also conducted using Western blot analysis. Following this, migration assays were performed using Boyden chamber to determine whether lovastatin has anti-migration effects in PC cells. Immunoprecipitation (IP) analyses were also performed to determine whether PRL-3 and Translationally Controlled Tumor Protein (TCTP) [a mediator of PRL-3 function] are binding partners using respective antibodies.

Our studies have shown lovastatin decreases the expression of PRL-3 resulting in the inhibition of DU145 cell proliferation; furthermore, a reduction in TCTP expression has also been observed in treated cells versus control cells. Specifically, lovastatin decreases the membrane localization of both PRL-3 and TCTP in DU145 cells. Moreover, IP results show that PRL-3 and TCTP are potential binding partners and this interaction may be critical for PC metastasis. Finally our results show that lovastatin has the ability to decrease the motility of DU145 PC cells in vitro. Taken together, our results for the first time show that lovastatin can target PRL-3 by interfering with prenylation and preventing the membrane location of PRL-3 and its downstream effector, TCTP in advanced prostate cancer cells. Targeting PRL-3 warrants further studies to develop PRL-3 as a therapeutic target for PC.

Citation Format: Allison K. Palmer, Gnanasekar Munirathinam. Effects of lovastatin on the PRL-3 cascade of events in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1766. doi:10.1158/1538-7445.AM2015-1766