Therapeutic implications of autophagy modulation in prostate cancer

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Autophagy is an evolutionarily conserved process implicated in degradation and recycling of proteins, carbohydrates, and lipids, in order to adapt cell metabolism to energy needs and lead to elimination of exhausted or unwanted organelles. This process is particularly relevant for removal of non-functional mitochondria, important source of reactive oxygen species (ROS) which can damage lipids, proteins, and DNA. When autophagy occurs, double-membrane vesicles named autophagosomes sequester cytosolic substrates initiating their lysosomic degradation (1). The role of autophagy in tumorigenesis is known to be much complex and context-dependent, leading to both cancer suppression and cancer progression. It may mediate tumor suppression possibly by removing damaged organelles which generate ROS and promote genotoxic stress. By contrast, autophagy may provide a survival advantage to tumor cells by helping to overcome the metabolic stress inherently present in the tumor microenvironment (2). Therefore, accurate modulation of autophagy appears to be a new paradigm in cancer therapeutics, opening new possibilities towards the identification of novel therapeutic approaches. For prostate cancer treatment, it is well known that androgen removal induces apoptosis and tumor regression being the rational of hormone ablation therapy (3). Therefore, the commonly used treatment of advanced prostate cancer is the inhibition of androgen production and/or androgen function. Although most patients (up to 50%) respond initially (4), the therapeutic effects often last only for a short period. In fact, cancer cells gradually develop towards an androgen-independent phenotype and survive by several mechanisms, including autophagy. Remarkably, two recent studies published in August 2012 by Kaini et al. and Bennett et al. demonstrate that the pharmacological autophagy blockade in the presence of androgen deprivation causes 40% cell death of epithelial prostate cancer LNCaP cells as compared to control conditions. Such effect has been obtained both through chloroquine (a well-known late-stage autophagy inhibitor, already tested in humans for different disorders) (5) and 3-methyladenine (an early-stage autophagy inhibitor) (6). Although in vivo studies on autophagy inhibition combined with androgen deprivation are still lacking, these new results sustain the potential therapeutic value of combining autophagy-modulation with conventional hormonal therapy in vivo. We have recently published that autophagic inhibition is also able to potentiate the apoptotic effect of tumor necrosis factor (TNF)-α (7). Increased apoptosis after TNF-α/3-methyladenine combined treatment was associated with reduced levels of the apoptotic inhibitor named c-Flip (8-10). Such result, while highlighting the importance of the autophagy inhibitor as potential therapeutic agent, further confirms the cross-talk existing between autophagy and apoptosis, through a shared mediator. Altogether, these considerations make clear that targeting autophagy may provide new opportunities for prostate cancer treatment, while there is an urgent need of novel potent and specific inhibitors of autophagy. High-throughput screening of chemical libraries as well as synthesis of new autophagy inhibitors impairing tumor growth in vivo are ongoing with encouraging results (11). Another promising field is now opening and arises from a deep analysis of the pathogens proteome, since some viruses have evolved strategies to interfere, escape or even exploit the autophagic machinery. We believe that these new approaches may help in rational drug design leading to new effective ways to modulate autophagy, ultimately potentiating cancer treatment.