Zoledronate acid modifies the lipid transporters profile in human prostate cancer cell lines

Abstract

21135 Background: The mechanism through wich zoledronic acid exerts its activity is poorly understood. Low density lipoprotein receptor (LDLR) and scavenger receptor class B type 1 (SRBI) overproduction is an important mechanism in cancer cells for obtaining more essential fatty acids and cell growth. The effects of in vitro zoledronate treatment on the lipid metabolism of prostate cancer cell lines were studied. Methods: Three prostatic cancer cell lines, androgen insensitive PC3, androgen dependent low-passage (LP) LNCaP and androgen independent high-passage (HP) LNCaP cells were studied. Cells were plated either in RPMI with 5% foetal calf serum and lipoprotein depleted serum (LPDS) and were treated with zoledronate at different concentrations. The lipid transporters profile was analyzed by western blotting for LDLR and SRB1. Results: The same LDLR bands profile was observed in all cell lines, 160 and 105 kDa. The basal levels of LDLR were higher in the PC3 cells. Zoledronate therapy induced LDLR expression in all cell lines but PC3 were less sensitive to this effect. Cells cultured with LPDS showed an enhanced expression of LDLR and PC3 cells were less sensitive to this effect. HP LNCaP cells were the most affected by lipoprotein deprivation however this effect diminished 72 hours after treatment. The bands profile for SRBI consisted of a 65 kDa predominant band and a 40 kDa band in both LP/HP LNCaP cells. In PC3 cells main band was located in 65 kDa and accessory band in 30kDa. The basal levels of the 65kDa band were higher in HP than in LP LNCaP or PC3 cells and zoledronate therapy caused a dose- dependent induction in HP LNCaP and dose-dependent reduction in PC3 cells, LP LNCaP cells were resistant to the treatment. LPDS induced SRBI levels in all cell lines inverting the effect caused by zoledronate in HP LNCaP cells in complete culture medium and at high doses (100μM) a complete inhibition of SRBI protein was found. Low molecular weight bands changed in the same way as the 65 kDa band. Conclusions: LDL-R and SRBI have been isolated in prostate cancer cell lines. Based on previous cell growth studies, the lipid transporters profile might be significantly involved in the resistance to zoledronate therapy. Lipoprotein regulation pathways should be considered in the therapy of metastatic prostate cancer. No significant financial relationships to disclose.