Novel Insights into Autophagy and Prostate Cancer: A Comprehensive Review

Abstract

Autophagy is a complex process involved in several cell activities, including tissue growth, differentiation, metabolic modulation, and cancer development. In prostate cancer, autophagy has a pivotal role in the regulation of apoptosis and disease progression. Several molecular pathways are involved, including PI3K/AKT/mTOR. However, depending on the cellular context, autophagy may play either a detrimental or a protective role in prostate cancer. For this purpose, current evidence has investigated how autophagy interacts within these complex interactions. In this article, we discuss novel findings about autophagic machinery in order to better understand the therapeutic response and the chemotherapy resistance of prostate cancer. Autophagic-modulation drugs have been employed in clinical trials to regulate autophagy, aiming to improve the response to chemotherapy or to anti-cancer treatments. Furthermore, the genetic signature of autophagy has been found to have a potential means to stratify prostate cancer aggressiveness. Unfortunately, stronger evidence is needed to better understand this field, and the application of these findings in clinical practice still remains poorly feasible.

Keywords: apoptosis; autophagy; cancer; castration-resistant prostate cancer; genes; neoplasia; prostate cancer; self-eating.

Figure 1

Metabolic activity and mitophagy. Decrease in energetic supply inhibits mTOR activity, which enhances autophagy. The energetic starvation leads to the loss of mitochondria membrane potential, associated to ROS overproduction. This condition activates PTEN-induced putative kinase 1 (PINK1) and the E3 ligase parkin (PARK2), which is able to ubiquitylate mitochondrial outer membrane proteins, providing recognition signals to the active autophagy machinery.

Figure 2

Autophagy and apoptosis interplay. Stress conditions can inhibit Bcl2 family through the phosphorylation of Bim/Bad/Bnip3. This condition results in liberation of Beclin1 and induction of autophagy, enhanced by the activation of c-Jun N-terminal kinases (JNKs). Subsequently, the oligomerization of the pro-apoptotic proteins BCL-2 antagonist killer 1 (BAK) and BCL-2-associated X protein (BAX) results in mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome C (Cyt C). Cyt C will form a complex with pro-caspases, resulting in Caspases activation and Cell death. Apoptosis and autophagy may also inhibit each other through protein cleavage.

Figure 3

Main pathways involved in autophagy regulation. PTEN and AMPK downregulate the PI3K/AKT/mTOR signaling pathway, to enhance autophagy. mTOR suppresses autophagy acting via P70S6K and STAT 3 expression. The activation of the EGFR/Ras/MEK/ERK pathway, JNK/cJun, and p38MAPK signaling pathways promotes autophagy. The Wnt/β-catenin signaling pathway attenuates Beclin1-mediated autophagy.

Figure 4

STK11/LKB1 expression is a predictive marker of response to p38MAPK inhibition in PCa. PCa cells with low/absent STK11/LKB1 expression undergo cell death after treatment with p38MAPK inhibitors. PCa cells expressing high levels of STK11/LKB1, show resistance to p38MAPK blockade, by activating autophagy. Conversely, inhibition of autophagy or of AMPK, triggers apoptosis in STK11/LKB1 expressing cells treated with p38MAPK inhibitors.