Autophagy as a modulator and target in prostate cancer

Abstract

Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.

Figures

Figure 1

Starvation and growth-factor deprivation stimulates cell signaling cascades (the key intermediates identified above) that ultimately result in the initiation of autophagy. The autophagosome matures and is trafficked to lysosomes where it fuses and creates the autolysosome. The autolysosome digests cellular biomass and eliminates toxins, facilitating a host of favorable nutrient and growth conditions. Modified from [15,64]

Figure 2

Depicts therapeutic interventions that either decrease total androgen or impede androgen receptor activity. The associated alterations in androgen receptor activity and down-stream synthetic capability influence autophagy, most notably through mTOR inhibition.

Figure 3

Depicts activation of Src kinase complex by epidermal growth factor (EGF), and cytokines Interleukin-6 (IL-6) and Interleukin-8 (IL-8). The Src kinase complex is composed of Src, Etk (A Btk tyrosine kinase family kinase) and FAK (Focal Adhesion Kinase) and undergoes cross-activation upon stimulation. The Src kinase complex negatively regulates autophagy and also promotes androgen independent growth. Modified from [63]

Figure 4

Arginine deiminase (ADI) hydrolyzes arginine into citrulline. To replenish arginine, cells utilize a two-step synthetic pathway involving argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). Prostate cancers deficient in either ASL or ASS will not be able to synthesize the necessary amount of arginine de novo. At this point, arginine deficiency can activate several different cellular metabolic pathways. Pathway A, AMPK is activated and mTOR is subsequently inhibited. This will promote autophagy. Pathway B, Bcl-2 is inhibited, freeing Beclin 1 to stimulate autophagy. Pathway C, Bcl-2 is once again inhibited, but in this case freeing Bak/Bax to activate apoptosis. Note: A longer duration of treatment ultimately promotes cell death – mediated by either apoptosis or pro-longed autophagy. Modified from [71,73]