Co-targeting SKP2 and KDM5B inhibits prostate cancer progression by abrogating AKT signaling with induction of senescence and apoptosis.

Background: Prostate cancer (PCa) is the second-leading cause of cancer mortalities in the United States and is the most commonly diagnosed malignancy in men. While androgen deprivation therapy (ADT) is the first-line treatment option to initial responses, most PCa patients invariably develop castration-resistant PCa (CRPC). Therefore, novel and effective treatment strategies are needed.

The KDM5 inhibitor PBIT reduces proliferation of castration-resistant prostate cancer cells via cell cycle arrest and the induction of senescence.

The compound 2-4(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one (PBIT) is an inhibitor of the KDM5 family of lysine-specific histone demethylases that has been suggested as a lead compound for cancer therapy. The goal of this study was to explore the effects of PBIT within human prostate cancers. Micromolar concentrations of PBIT altered proliferation of castration-sensitive LNCaP and castration-resistant C4-2B, LNCaP-MDV3100 and PC-3 human prostate cancer cell lines.

The Tennessee Center for AIDS Research HIV Research Training Program for Minority High School and Undergraduate Students: Development, Implementation, and Early Outcomes.

Background: The Southern region of the United States has the highest HIV incidence, and new infections disproportionately affect Black Americans. The Tennessee Center for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI) program supports the training of individuals from groups underrepresented in medicine and science in multiple areas of research to increase the pool of HIV-focused investigators at early educational and career stages.

Setting: The Tennessee CFAR is a partnership between Vanderbilt University Medical Center, Meharry Medical College (one of the oldest historically Black medical colleges), Tennessee Department of Health, and Nashville Community AIDS Resources, Education and Services (a sophisticated community service organization, which emphasizes research training responsive to regional and national priorities).

Hypoxia-Inducible Expression of Annexin A6 Enhances the Resistance of Triple-Negative Breast Cancer Cells to EGFR and AR Antagonists.

Physiological changes such as hypoxia in the tumor microenvironment (TME) endow cancer cells with malignant properties, leading to tumor recurrence and rapid progression. Here, we assessed the effect of hypoxia (1% Oxygen) on the tumor suppressor Annexin A6 (AnxA6) and the response of triple-negative breast cancer (TNBC) cells to epidermal growth factor receptor (EGFR) and androgen receptor (AR) targeted therapies. We demonstrate that brief exposure of TNBC cells to hypoxia (within 24 h) is associated with down regulation of AnxA6 while > 24 h exposure cell type dependently stimulated the expression of AnxA6.

Metformin regulates multiple signaling pathways within castration-resistant human prostate cancer cells.

Background: The biguanide metformin has been shown to not only reduce circulating glucose levels but also suppress in vitro and in vivo growth of prostate cancer. However, the mechanisms underlying the anti-tumor effects of metformin in advanced prostate cancers are not fully understood. The goal of the present study was to define the signaling pathways regulated by metformin in androgen-receptor (AR) positive, castration-resistant prostate cancers.

Crosstalk between the Androgen Receptor and PPAR Gamma Signaling Pathways in the Prostate.

Nuclear receptors are a superfamily of ligand-activated transcription factors that play critical roles in the regulation of normal biological processes and several disease states. Of the nuclear receptors expressed within the prostate, the androgen receptor (AR) promotes the differentiation of prostatic epithelial cells and stimulates production of enzymes needed for liquefaction of semen. Multiple forms of AR also promote the growth of both early and late stage prostate cancers.

The Androgen Receptor Regulates PPARγ Expression and Activity in Human Prostate Cancer Cells.

The peroxisome proliferator activated receptor gamma (PPARγ) is a ligand-activated transcription factor that regulates growth and differentiation within normal prostate and prostate cancers. However the factors that control PPARγ within the prostate cancers have not been characterized. The goal of this study was to examine whether the androgen receptor (AR) regulates PPARγ expression and function within human prostate cancer cells.

Troglitazone suppresses c-Myc levels in human prostate cancer cells via a PPARγ-independent mechanism.

Troglitazone is a ligand for the peroxisome proliferator activated receptor gamma (PPARγ) that decreases growth of human prostate cancer cells in vitro and in vivo. However, the mechanism by which troglitazone reduces prostate cancer cell growth is not fully understood. To understand the signaling pathways involved in troglitazone-induced decreases in prostate cancer growth, we examined the effect of troglitazone on androgen-independent C4-2 human prostate cancer cells.

The PPARγ ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells.

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPARγ ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPARγ ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line.

Thiazolidinediones regulate expression of cell cycle proteins in human prostate cancer cells via PPARgamma-dependent and PPARgamma-independent pathways.

Thiazolidinediones (TZDs) are peroxisome proliferator activated receptor gamma (PPARgamma) ligands that have been reported to reduce proliferation of human prostate cancer cells. However, the mechanisms by which TZDs inhibit prostate cancer cell proliferation are not fully understood. In addition, it is not known if the anti-proliferative effects of TZDs require activation of PPARgamma or are mediated by PPARgamma-independent pathways.

Vitamin D receptor agonists induce prostatic acid phosphatase to reduce cell growth and HER-2 signaling in LNCaP-derived human prostate cancer cells.

We have previously shown that concentrations of 1alpha,25-dihydroxyvitamin D(3) (1,25D) that induce G(0)/G(1) cell cycle arrest in androgen-dependent LNCaP prostate cancer cells also decrease expression of c-Myc, a proto-oncogene that stimulates progression from G(1) to S phase of the cell cycle. Since both c-Myc expression and cell cycle progression are regulated by tyrosine kinase activation, we examined the ability of 1,25D to alter tyrosine kinase signaling in LNCaP cells and the androgen-independent LNCaP C81 (C81 LN) cell line. 1,25D selectively reduced protein tyrosine phosphorylation within both the LNCaP and C81 LN cells.

Vitamin D and prostate cancer.

Vitamin D and its metabolites are best known for their actions in calcium and bone metabolism. However, epidemiological studies have suggested that an increased prostate cancer risk is associated with decreased production of vitamin D. In vitro and in vivo studies have shown that the biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25D), inhibits proliferation of cancer cells derived from multiple tissues, including the prostate.

Regulation of trespin expression by modulators of cell growth, differentiation, and apoptosis in prostatic epithelial cells.

We recently identified a novel rat ov-serpin, Trespin, which inhibits the trypsin-like serine proteinase plasmin and is expressed in several tissues, including prostate. In this report Trespin expression was studied in prostatic cell lines, NRP-152, NRP-154, and DP-153, derived from the Lobund-Wistar rat. Northern blots revealed Trespin mRNA is expressed in NRP-152 and DP-153 basal epithelial cell lines but not in the luminal line, NRP-154.

p53 Is required for 1,25-dihydroxyvitamin D3-induced G0 arrest but is not required for G1 accumulation or apoptosis of LNCaP prostate cancer cells.

1,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] is an effective agent for inhibiting the growth of prostate cancer cells including LNCaP and PC-3 cell lines. However, the extent of growth inhibition in these cell lines differs because LNCaP cells are much more responsive than PC-3 cells. Previous studies in LNCaP cells have shown that 1,25-(OH)(2)D(3) treatment results in G(0)/G(1) cell cycle accumulation, loss of Ki67 expression, and induction of apoptosis.