In summary our findings indicate that bFGF stimulates CPT
In summary, our findings indicate that bFGF stimulates CPT1 expression, FA oxidation and lactate production with the participation of PPARβ/δ activation. On the other hand, this investigation shows that FSH concomitantly regulates the expression of genes involved in FA metabolism and in mitochondrial biogenesis in Sertoli Capecitabine independently of PPARβ/δ activation. Metabolic processes such as FA oxidation, mitochondrial biogenesis and lactate production in Sertoli cells are essential for the energetic metabolism of the seminiferous tubule. The fact that these processes are regulated by hormones in a different way reflects the multifarious regulation of molecular mechanisms involved in Sertoli cell function.
Declaration of interest
Funding This work was supported by Grants from the Consejo Nacional de Investigaciones Cientificas y Técnicas (CONICET) (PIP 2011/187) and from the Agencia Nacional de Promoción Científica y Tecnológica (PICT 2011/677) and (PICT 2012/666).
Introduction Drugs targeting tumor blood vessels are commonly used in cancer patients and they generally produce limited therapeutic benefits for survival improvement (Cao et al., 2011). One of the main hitches of low therapeutic efficacy is that cancer patients often develop resistance in response to antiangiogenic drug (AAD) treatment (Bergers and Hanahan, 2008, Cao and Langer, 2010, Cao et al., 2009, Casanovas et al., 2005, Chung et al., 2013, Crawford et al., 2009). Patients with cancers grown in organs adjacent to adipose tissues, including breast cancer, prostate cancer, pancreatic cancer, and hepatocellular carcinoma (HCC), show particularly low benefits from antiangiogenic therapy. These cancers located adjacent to adipose tissues often show intrinsic or acquired resistance to antiangiogenic therapy. For example, most patients with pancreatic ductal adenocarcinoma (PDAC) show intrinsic resistance and colorectal cancer (CRC) patients exhibit evasive resistance to bevacizumab (Van Cutsem et al., 2009). A puzzling observation in the field of antiangiogenic cancer therapy has been the inconsistency of drug effects in preclinical animal models and in cancer patients (Cao et al., 2011). While most AADs produce overwhelming anti-tumor effects in mouse models, the same drug often lacks anti-cancer effect in human patients. Among numerous possible reasons, the location of tumor implantation in animal models is often different from clinical situations. For example, subcutaneous implantation is a common location for studying animal tumors for the sake of convenience in monitoring tumor growth. However, human tumors rarely originate from a subcutaneous location. Tumor tissues often experience hypoxia owing to accelerated growth rates of malignant cells, accumulation of metabolic products, disorganization of tumor blood vessels, and high interstitial fluid pressures (Makino et al., 2001). In response to AAD treatment, tumor vascular density often decreases to an extremely low level, creating an elevated hypoxic environment (Rapisarda and Melillo, 2012). It is known that tumor hypoxia can exacerbate expression levels of growth factors and cytokines, which circumvent the drug targets and create possible resistance (Casanovas et al., 2005). Hypoxia may also change the composition of various cell types within the tumor microenvironment (TME), leading to alteration of cancer invasiveness and drug responses (Cao et al., 2009). Unlike most healthy cells, cancer cells exhibit distinctive features of uncontrolled cell proliferation (Hanahan and Weinberg, 2011). To cope with the unlimited growth, expansion, and dissemination, cancer cells must efficiently produce energy, even in poorly oxygenated and nutrient-scarce microenvironments (Beloribi-Djefaflia et al., 2016). Cancer cells show exacerbated glucose uptake and glycolysis-dependent metabolism (i.e., the Warburg effect; Warburg, 1956). In addition, malignant cells also rely on glutamine consumption to obtain carbon, amino-nitrogen for producing nucleotides, amino acids, and lipid biosynthesis. Recent studies show that highly proliferative cancer cells have lipogenic activity by uptake of exogenous lipids and activating endogenous lipid biosynthesis (Beloribi-Djefaflia et al., 2016). Utilization of exogenous free fatty acids (FFAs) for energy production through the fatty acid oxidation (FAO) metabolic pathway is prominent in non-glycolytic cancers such as prostate cancer and B cell lymphoma (Caro et al., 2012, Liu et al., 2010). Several lipogenic enzymes, including acetyl coenzyme A carboxylase and fatty acid synthase (FASN), are often increased in invasive tumors and their expression levels correlate with poor prognosis (Kuhajda, 2006). The FAO-limiting enzyme, CPT1 (A and C types), is often overexpressed in many human tumors (Reilly and Mak, 2012). It is known that adipose tissue and FFA significantly contribute to cancer cell survival, proliferation, and migration (Lazar et al., 2016, Nieman et al., 2011). Previously published work also showed that anti-VEGF treatment and tissue hypoxia increase lipid transport and storage through an HIF-1α-dependent mechanism in cancer cells (Bensaad et al., 2014).