In this current issue, Kaittanis et al

In this current issue, Kaittanis et al. treatment. However, despite clear clinical benefits, most patients ultimately develop resistance to these drugs and relapse. Although the mechanisms behind the development of CRPC are not yet fully understood, the consensus is that canonical sources of androgens are being replaced through genetic and nongenetic mechanisms, which continue to fuel tumor growth (Rodon et al., 2013). One of the nongenetic pathways involved in the development of CRPC is the phosphoinositide 3-kinase (PI3K) pathway, which is commonly deregulated in various human cancers. The PI3KCAKTCmTOR axis is abnormally activated in 70C100% of advanced prostate cancer patients (100% of CRPC patients; Taylor et al., 2010). This constitutive activation is attributed to loss of phosphatase and tensin homologue (PTEN), which has been shown to play an important role in the development of AR-independent metastatic carcinoma (Wang et al., 2003). The tumor enhancing activity of PI3K in a PTEN-deficient background seems to be dependent on its p110 catalytic isoform, rather than the p110 isoform, more commonly mutated in human cancers (Jia et al., 2008). A solid body of evidence supports the establishment of a reciprocal feedback loop between the AR signaling pathway and the PI3K axis, which explains, at least in part, the cIAP1 ligand 1 development of CRPC and resistance to various therapeutic agents targeting cIAP1 ligand 1 these pathways. In this model, inhibition of PI3K in a PTEN-deficient background activates AR signaling, and vice-versa, inhibiting AR signaling activates PI3K-dependent AKT phosphorylation (Carver et al., 2011; Mulholland et al., 2011). This reciprocal negative feedback loop between AR and PI3K signaling remains a major challenge for future therapies targeting prostate cancer. In this current issue, Kaittanis et al. discover a new avenue to further our understanding of the mechanisms behind the AR-PI3K dynamics and the development of CRPC, consequently identifying a novel targetable oncogenic signaling cascade. Prostate-specific membrane antigen (PSMA) has become a popular target for developing new diagnosis tools designed to improve stratification of patients for targeted personalized therapeutic regimens (Pillai et al., 2016). PSMA is moderately expressed in several tissues, including healthy prostate tissue; however, it is greatly up-regulated in prostate cancer (Israeli et al., 1994). PSMA has two types of catalytic activities: NAALDase and folate hydrolase, both resulting in the release of glutamate from the enzyme substrates. Its capacity to release glutamate form em N /em -acetyl-l-aspartyl-glutamate (NAAG) is being explored for its therapeutic potential for brain ischemic injury and several neurodegenerative disorders. Kaittanis et al. (2018) investigate the folate hydrolase activity of PSMA in prostate cancer, its cIAP1 ligand 1 biological function (uncharted thus far), and, most importantly, its potential as a therapeutic target (see figure). Open in a separate window PSMA: A versatile tool for prostate cancer therapy. PSMA is expressed with high specificity at the membrane of prostate Rabbit polyclonal to ACVR2B cancer cells. Through its unique position and enzymatic function, it constitutes a notable target for radiolabeling. Because of its strict correlation with AKT expression, it could prove to be the ideal tool cIAP1 ligand 1 for diagnosis and patient stratification. Moreover, targeting PSMA inhibits cIAP1 ligand 1 PI3K signaling in prostate cancer cells; thus, combinatorial approaches with androgen pathway inhibitors and PSMA inhibitors could lead to a powerful therapeutic tool, overcoming the off-target toxic effects associated with other therapies, such as PI3K inhibitors. Combining these two applications may pave the way toward.