PubMed · 3926355
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D J Handelsman, R S Swerdloff. 1985. Male gonadal dysfunction.. https://doi.org/10.1016/s0300-595x(85)80066-9
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Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGCα1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1 (-/-)S6 than of male sGCα1 (-/-)B6 mice. Furthermore, treating male sGCα1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCα1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCα1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
BACKGROUND: Prostate cancer is the most commonly diagnosed neoplasm and the second leading cause of male death in this country. Multiple genetic and epigenetic factors have been implicated in the oncogenesis and progression of prostate cancer. However, the molecular mechanisms underlying the disease remain largely unknown. The major difficulty in the clinical management of prostate cancer stems from the reality that reliable and accurate diagnostic/prognostic biomarkers are not available and that effective treatment regimens for hormone-resistant prostate cancers are yet to be developed. METHODS: The present review, through extensive literature research, summarizes the most recently accumulated experimental and clinical data on the relationship between apoptosis and prostate cancer. We analyze the possibility of inducing prostate cancer cell apoptosis by: 1) androgen ablation by castration or biochemical antagonists: 2) chemotherapeutic drugs or natural/synthetic chemicals; 3) manipulation of apoptosis-related oncoproteins; and 4) modulation of intracellular signal transducers. RESULTS: 1) Prostate cancer, like most other solid tumors, represents a very heterogeneous entity. Most prostate cancers, at the time of clinical diagnosis, present themselves as mixtures of androgen-dependent and androgen-independent cells. 2) Most prostate cancers respond initially to androgen ablation since the population of androgen-dependent cells undergoes rapid apoptosis upon androgen withdrawal. However, androgen ablation rarely cures patients, most of whom will experience recurrence due to takeover of the tumor mass by androgen-independent tumor cells as well as the emergence of apoptosis-resistant clones as a result of further genetic alterations such as bcl-2 amplification. 3) On the other hand, although androgen-independent prostate cancer cells do not undergo apoptosis upon androgen blocking, they do maintain the appropriate molecular machinery of apoptosis. Therefore, certain conventional chemotherapy drugs can eliminate androgen-independent cancer cells by inducing apoptosis. 4) However, most drugs used in chemotherapy induce apoptosis or mediate cytotoxicity only in proliferating cancer cells. Human prostate cancer cells demonstrate very slow growth kinetics. Thus, novel chemical/natural products need be identified to eradicate those nonproliferating cancer cells. In this regard, the angiogenesis inhibitor, linomide, and a plant extract, beta-lapachone, demonstrate very promising apoptosis-inducing effects on prostate cancer cells in a proliferation-independent manner. 5) An alternative way to modulate the apoptotic response is by interfering with the expression levels of essential regulatory molecule of apoptosis. Bcl-2 and p53 represent two prime targets for such manipulations. 6) Finally, modulation of signal transduction pathways (e.g., intracellular Ca2+ levels, PKC activity) involved in apoptosis may also induce and/or enhance the apoptotic response of prostate cancer cells. CONCLUSIONS: Modulation of apoptotic response represents a novel mechanism-based approach which may help identify novel drugs and/or develop new therapeutic regimens for the treatment of prostate cancers.
Cellular interactions between stroma and epithelium are important in the growth and proliferation of prostate cancer. Peptide growth factors may facilitate the progression of prostate cancer as autocrine and/or paracrine factors. Keratinocyte Growth Factor (KGF or FGF7) has a differentiative and proliferative effect on the epithelium of the developing rat prostate. We investigated if KGF may act as a paracrine agent in human prostate cancer and examined the expression of KGF and Fibroblast Growth Factor Receptors (FGFRs) (IIIb and IIIc isoforms of the FGFR1 and FGFR2 genes). Sixty-five percent (11 out of 17 informative cases) of prostate cancers (CaP) expressed KGF mRNA by RT-PCR, while KGF expression was not detected in benign prostatic hyperplasia (BPH) (n = 6). Upregulation of KGF expression was related to hormone insensitive tumours (P<0.05). Tumour grade and stage were not associated with KGF expression. The source of KGF expression was further characterised using an in vitro primary culture model, showing its restriction to the prostatic stroma. The FGFR1IIIb isoform was expressed in all cases of prostate cancer (n = 17), and FGFR1IIIc mRNA was not detected. In the BPH group, FGFR1IIIb transcripts were detected in four out of six cases. FGFR2IIIb expression was detected in five of six cases of BPH and twelve out of seventeen (71%) cases of prostate cancer. In CaP, though not reaching statistical significance, the persistence of FGFR2IIIb expression appeared to be associated with hormone insensitive tumours (P=0.052). FGFR2IIIc expression was present in eleven of seventeen tumours but was absent in all six cases of BPH. Functional assessment of recombinant KGF in a proliferation assay demonstrated a mitogenic effect of up to 100% on cultured prostatic epithelial cells.