Search

The omega-3 long chain polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), elicit anti-proliferative effects in cancer cell lines and in animal models. Dietary DHA and EPA can be converted to their ethanolamide derivatives, docosahexaenoyl ethanolamine (DHEA), and eicosapentaenoyl ethanolamine (EPEA), respectively; however, few studies are reported on their anti-cancer activities. Here, we demonstrated that DHEA and EPEA were able to reduce cell viability in MCF-7 breast cancer cells whereas they did not elicit any effects in MCF-10A non-tumorigenic breast epithelial cells. Since DHA and EPA are ligands of peroxisome proliferator-activated receptor gamma (PPARγ), we sought to determine whether PPARγ may also mediate DHEA and EPEA actions. In MCF-7 cells, both compounds enhanced PPARγ expression, stimulated a PPAR response element-dependent transcription as confirmed by the increased expression of its target gene PTEN, resulting in the inhibition of AKT-mTOR pathways. Besides, DHEA and EPEA treatment induced phosphorylation of Bcl-2 promoting its dissociation from beclin-1 which resulted in autophagy induction. We also observed an increase of beclin-1 and microtubule-associated protein 1 light chain 3 expression along with an enhanced autophagosomes formation as revealed by mono-dansyl-cadaverine staining. Finally, we demonstrated the involvement of PPARγ in DHEA- and EPEA-induced autophagy by using siRNA technology and a selective inhibitor. In summary, our data show that the two omega-3 ethanolamides exert anti-proliferative effects by inducing autophagy in breast cancer cells highlighting their potential use as breast cancer preventive and/or therapeutic agents., (Copyright © 2012 Wiley Periodicals, Inc.)

Breast cancer is the most frequent tumor and a major cause of death among women. Estrogens play a crucial role in breast tumor growth, which is the rationale for the use of hormonal antiestrogen therapies. Unfortunately, not all therapeutic modalities are efficacious and it is imperative to develop new effective antitumoral drugs. Oldenlandia diffusa (OD) is a well-known medicinal plant used to prevent and treat many disorders, especially cancers. The aim of this study was to investigate the effects of OD extracts on breast cancer cell proliferation. We observed that OD extracts strongly inhibited anchorage-dependent and -independent cell growth and induced apoptosis in estrogen receptor alpha (ERα)-positive breast cancer cells, whereas proliferation and apoptotic responses of MCF-10A normal breast epithelial cells were unaffected. Mechanistically, OD extracts enhance the tumor suppressor p53 expression as a result of an increased binding of ERα/Sp1 complex to the p53 promoter region. Finally, we isolated ursolic and oleanolic acids as the bioactive compounds able to upregulate p53 expression and inhibit breast cancer cell growth. These acids were greatly effective in reducing tamoxifen-resistant growth of a derivative MCF-7 breast cancer cell line resistant to the antiestrogen treatment. Our results evidence how OD, and its bioactive compounds, exert antiproliferative and apoptotic effects selectively in ERα-positive breast cancer cells, highlighting the potential use of these herbal extracts as breast cancer preventive and/or therapeutic agents., (Copyright © 2011 Wiley Periodicals, Inc.)

Several substances such as anabolic androgenic steroids (AAS), peptide hormones like insulin-like growth factor-I (IGF-I), aromatase inhibitors and estrogen antagonists are offered via the Internet, and are assumed without considering the potential deleterious effects that can be caused by their administration. In this study we aimed to determine if nandrolone and stanozolol, two commonly used AAS, could have an effect on Leydig cell tumor proliferation and if their effects could be potentiated by the concomitant use of IGF-I. Using a rat Leydig tumor cell line, R2C cells, as experimental model we found that nandrolone and stanozolol caused a dose-dependent induction of aromatase expression and estradiol (E2) production. When used in combination with IGF-I they were more effective than single molecules in inducing aromatase expression. AAS exhibited estrogenic activity and induced rapid estrogen receptor (ER)-dependent pathways involving IGF1R, AKT, and ERK1/2 phosphorylation. Inhibitors for these kinases decreased AAS-dependent aromatase expression. Up-regulated aromatase levels and related E2 production increased cell proliferation as a consequence of increased cyclin E expression. The observation that ER antagonist ICI182,780 was also able to significantly reduce ASS- and AAS + IGF-induced cell proliferation, confirmed a role for estrogens in AAS-dependent proliferative effects. Taken together these data clearly indicate that the use of high doses of AAS, as it occurs in doping practice, enhances Leydig cell proliferation, increasing the risk of tumor development. This risk is higher when AAS are used in association with IGF-I. To our knowledge this is the first report directly associating AAS and testicular cancer., (Copyright © 2011 Wiley Periodicals, Inc.)

Obesity is a risk factor for endometrial cancer in pre- and post-menopausal women. Leptin, an adipocyte-derived hormone, in addition to the control weight homeostasis, is implicated in multiple biological actions. A recent study demonstrated that leptin promotes endometrial cancer growth and invasiveness through STAT/MAPK and Akt pathways, but the molecular mechanism involved in such processes still needs to be elucidated. In an attempt to understand the role of leptin in regulating endometrial cancer cells proliferation, we have demonstrated that leptin treatment reduced the numbers of cells in G0/G1-phase while increased cell population in S-phase. This effect is associated with an up-regulation of cyclin D1 together with a down-regulation of cyclin-dependent kinase inhibitor p21(WAF1/Cip1). Mutagenesis studies, eletrophoretic mobility shift, and chromatin immunoprecipitation analysis revealed that signal transducers and activators of transcription 3 (STAT3) and cyclic AMP-responsive element (CRE) binding protein motifs, within cyclin D1 promoter, were required for leptin-induced cyclin D1 expression in Ishikawa endometrial cancer cells. Silencing of STAT3 and CREB gene expression by RNA interference reversed the up-regulatory effect of leptin on cyclin D1 expression and cells proliferation. These results support the hypothesis that STAT3 and CREB play an important role in leptin signaling pathway that leads to the proliferation of Ishikawa cells, thus establishing a direct association between obesity and endometrial tumorogenesis.

The testis is an immunologically privileged site of the body where Sertoli cells work on to favor local immune tolerance by testicular autoantigens segregation and immunosuppressive factors secretion. Fas/Fas Ligand (FasL) system, expressed prevalently in Sertoli cells, has been considered to be one of the central mechanisms in testis immunological homeostasis. In different cell lines it has been reported that the proapoptotic protein FasL is regulated by 17-beta estradiol (E2). Thus, using as experimental model mouse Sertoli cells TM4, which conserve a large spectrum of functional features present in native Sertoli cells, like aromatase activity, we investigated if estradiol "in situ" production may influence FasL expression. Our results demonstrate that an aromatizable androgen like androst-4-ene-3,17-dione (Delta4) enhanced FasL mRNA, protein content and promoter activity in TM4 cells. The treatment with N(6),2'-O-dibutyryladenosine-3'-5'-cyclic monophosphate [(Bu)(2)cAMP] (simulating FSH action), that is well known to stimulate aromatase activity in Sertoli cells, amplified Delta4 induced FasL expression. Functional studies of mutagenesis, electrophoretic mobility shift (EMSA) and chromatin immunoprecipitation (ChIP) assays revealed that the Sp-1 motif on FasL promoter was required for E2 enhanced FasL expression in TM4 cells. These data let us to recruit FasL among those genes whose expression is up-regulated by E2 through a direct interaction of ERalpha with Sp-1 protein. Finally, evidence that an aromatizable androgen is able to increase FasL expression suggests that E2 production by aromatase activity may contribute to maintain the immunoprivilege status of Sertoli cells., ((c) 2007 Wiley-Liss, Inc.)

The peroxisome proliferation-activated receptor gamma (PPARgamma) is mainly expressed in the adipose tissue and integrates the control of energy, lipid, and glucose homeostasis. The present study, by means of RT-PCR, Western blot, and immunofluorescence techniques, demonstrates that human sperm express the PPARgamma. The functionality of the receptor was evidenced by 15-deoxy-12,14-prostaglandin J(2) (PGJ2) and rosiglitazone (BRL) PPARgamma-agonists that were tested on capacitation, acrosome reaction, and motility. Both treatments also increase AKT phosphorylations and influence glucose and lipid metabolism in sperm. The specificity of PGJ2 and BRL effects through PPARgamma on human sperm was confirmed by an irreversible PPARgamma antagonist, GW9662. Our findings provide evidence that human sperm express a functional PPARgamma whose activation influences sperm physiology. In conclusion, the presence of PPARgamma in male gamete broadens the field of action of this nuclear receptor, bringing us to look towards sperm as an endocrine mobile unit independent of the systemic regulation., ((c) 2006 Wiley-Liss, Inc.)