FAM3B/PANDER inhibits cell death and increases prostate tumor growth by modulating the expression of Bcl-2 and Bcl-X-L cell survival genes
Authors: Maciel-Silva, Paula; Caldeira, Izabela; Santos, Icaro de Assis; Oliveira Carreira, Ana Claudia; Siqueira, Flavia Ramos; Antonioli, Eliane; Goldberg, Anna Carla; Belizario, Jose Ernesto; Garay-Malpartida, Humberto Miguel
Background: FAM3B/PANDER is a novel cytokine-like protein that induces apoptosis in insulin-secreting beta-cells. Since in silico data revealed that FAM3B can be expressed in prostate tumors, we evaluated the putative role of this cytokine in prostate tumor progression. Methods: FAM3B expression was analyzed by quantitative PCR in tumor tissue clinical samples and prostate tumor cell lines. Culture growth and viability of DU145 cell line were evaluated after treatment with either exogenous FAM3B protein obtained from conditioned media (CM) of 293 T cells overexpressing FAM3B or a recombinant FAM3B protein produced in a bacterial host. DU145 cells overexpressing FAM3B protein were produced by lentiviral-mediated transduction of full-length FAM3B cDNA. Cell viability and apoptosis were analyzed in DU145/FAM3B cells after treatment with several cell death inducers, such as TNF-alpha, staurosporine, etoposide, camptothecin, and serum starvation conditions. Anchorage-independent growth in soft agarose assay was used to evaluate in vitro tumorigenicity. In vivo tumorigenicity and invasiveness were evaluated by tumor xenograft growth in nude mice. Results: We observed an increase in FAM3B expression in prostate tumor samples when compared to normal tissues. DU145 cell viability and survival increased after exogenous treatment with recombinant FAM3B protein or FAM3B-secreted protein. Overexpression of FAM3B in DU145 cells promoted inhibition of DNA fragmentation and phosphatidylserine externalization in a time and dose-dependent fashion, upon apoptosis triggered by TNF-alpha. These events were accompanied by increased gene expression of anti-apoptotic Bcl-2 and Bcl-XL, decreased expression of pro-apoptotic Bax and diminished caspase-3, -8 and -9 proteolytic activities. Furthermore, inhibition of Bcl-2 antiapoptotic family proteins with small molecules antagonists decreases protective effects of FAM3B in DU145 cells. When compared to the respective controls, cells overexpressing FAM3B displayed a decreased anchorage-independent growth in vitro and increased tumor growth in xenografted nude mice. The immunohistochemistry analysis of tumor xenografts revealed a similar anti-apoptotic phenotype displayed by FAM3B-overexpressing tumor cells. Conclusions: Taken together, by activating pro-survival mechanisms FAM3B overexpression contributes to increased resistance to cell death and tumor growth in nude mice, highlighting a putative role for this cytokine in prostate cancer progression.
Effects of circulating member B of the family with sequence similarity 3 on the risk of developing metabolic syndrome and its components: A 5-year prospective study
JOURNAL OF DIABETES INVESTIGATION
Authors: Wang, Haoyu; Yu, Fadong; Zhang, Zhuo; Hou, Yuanyuan; Teng, Weiping; Shan, Zhongyan; Lai, Yaxin
Aims/IntroductionMember B of the family with sequence similarity 3 (FAM3B), also known as pancreatic-derived factor, is mainly synthesized and secreted by islet -cells, and plays a role in abnormal metabolism of glucose and lipids. However, the prospective association of FAM3B with metabolic disorders remains unclear. The present study aimed to reveal the predictive relationship between pancreas-specific cytokine and metabolic syndrome (MetS). Materials and MethodsA total of 210 adults (88 men and 122 women) without MetS, aged between 40 and 65 years, were recruited and received a comprehensive health examination. Baseline serum FAM3B levels were determined by sandwich enzyme-linked immunosorbent assay. Subsequently, all participants underwent a follow-up examination after 5 years. MetS was identified in accordance with the International Diabetes Federation criteria. ResultsDuring follow up, 35.7% participants developed MetS. In comparison with the non-MetS group, participants with MetS had an increased serum FAM3B at baseline (21.85 ng/mL [19.38, 24.17 ng/mL] vs 28.56 ng/mL [25.32, 38.10 ng/mL], P < 0.001). Moreover, serum FAM3B was significantly associated with variations in fasting plasma insulin (r = -0.306, P < 0.001), homeostasis model assessment of -cell function (r = -0.328, P < 0.001) and homeostasis model assessment of insulin resistance (r = -0.191, P = 0.006). Furthermore, a positive correlation between baseline FAM3B and the incidence of MetS was observed, even after multivariable adjustment (relative risk 1.23 [1.15, 1.31], P < 0.001). Furthermore, the optimal cut-off values of FAM3B was 23.98 ng/mL for predicting MetS based on the Youden Index. ConclusionsElevated circulating FAM3B might be considered as a predictor of newly-onset MetS and its progression.