Lovastatin-Induced Apoptosis in Prostate Stromal Cells

Abstract

Benign prostatic hyperplasia (BPH) is a common disease of aging men. Current medical treatment for this condition is only partially effective, therefore many patients must undergo surgery for symptomatic relief. BPH is caused by an increase in prostate epithelial and stromal cells, especially the latter. Since BPH stromal cells have a long life span and are not very responsive to androgen withdrawal, cultured BPH stromal cells were used to explore the feasibility of pharmacologically inducing apoptosis in these cells. We obtained BPH tissue during surgery, and stromal cells were isolated and maintained in culture. After cells achieved confluence, we induced apoptosis with the HMGCoA reductase inhibitor, lovastatin (30 micromol/L). The effects of testosterone (100 micromol/L), dihydrotestosterone (DHT; 100 micromol/L) and finasteride (100 micromol/L) on lovastatin-induced apoptosis were studied on cells grown in media containing charcoal stripped serum. Similarly, we examined the effect of the cholesterol pathway metabolites, mevalonic acid (30 micromol/L), geranyl geraniol (30 micromol/L), farnesol (10 micromol/L), squalene (30 micromol/L) and 7-ketocholesterol (3 micromol/L) on lovastatin-induced apoptosis. We demonstrated apoptosis by DNA laddering in agarose gels, by fluorescence microscopy following acridine orange staining, and by flow cytometry after end-labeling of DNA strand breaks with biotin-16-dUTP using deoxynucleotidyl exotransferase (TdT). Lovastatin at 30 micromol/L, but not at lower concentrations, induced apoptosis in BPH prostate stromal cells. This was seen (by flow cytometry) in 16.6 +/- 7.3% (mean +/- SD) of BPH cells treated with lovastatin at 72 h vs. 2.5 +/- 1.2% of cells treated with ethanol. Lovastatin-induced apoptosis was not increased in stripped serum or by the addition finasteride, and was not inhibited by testosterone or DHT. Only mevalonate and geranyl geraniol, prevented lovastatin-induced apoptosis whereas farnesol, squalene, or 7-ketocholesterol did not. We conclude that lovastatin can induce apoptosis in BPH stromal cells in vitro, and this is not affected by androgen withdrawal or stimulation. It is unlikely that lovastatin, per se, will be an effective treatment for BPH in vivo, but it does provide a means for inducing apoptosis in vitro. Understanding the apoptotic process in BPH stromal cells ultimately may lead to new therapeutic strategies for BPH.

Current models of human prostate contractility

“…64,65 In more recent times, human cultured prostatic stromal cells have gained credence in the investigation of prostatic stromal contractility, [66][67][68] second messenger pathway activity, 67,69,70 proliferation 71,72 and apoptosis. 73,74 Given the abundance of studies showing biological effects in both whole tissue and cultured cells, it seems appropriate to address the obvious question of how suitable cultured stromal cells are as a model of intact prostatic tissue.…”

Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells

“…35 Some investigations have shown that lovastatin induces apoptotic cell death through the block of geranylgeranylated and/or farnesylated proteins in different cell types. For example, GGPP or geranyl geraniol completely prevents lovastatininduced apoptosis in mouse proximal tubular cells, 18 colon cancer cells, 25 prostate stromal cells, 36 and rat pulmonary vascular smooth muscle cells. 37 It has been shown that the geranylgeranylated Rho family members play important roles in cellular signal transduction and possess dual roles in cell proliferation and apoptosis.…”

Statin Use and Risk of Prostate Cancer in the California Men's Health Study Cohort

“…Additionally, substantial laboratory data indicate that statins may function as anticancer agents through proapoptotic, antiangiogenic, and antimetastatic processes (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). However, the results of individual randomized controlled trials (35)(36)(37)(38)(39)(40)(41), as well as those from systematic reviews of large trials (42)(43)(44)(45)(46), do not support an association between statins and cancer risk, although the number of cancers at any specific site, including the prostate, have been small and the followup time has been short.…”