Targeting autophagy in prostate cancer: preclinical and clinical evidence for therapeutic response

Abstract

Prostate cancer is a leading cause of death worldwide and new estimates revealed prostate cancer as the leading cause of death in men in 2021. Therefore, new strategies are pertinent in the treatment of this malignant disease. Macroautophagy/autophagy is a "self-degradation" mechanism capable of facilitating the turnover of long-lived and toxic macromolecules and organelles. Recently, attention has been drawn towards the role of autophagy in cancer and how its modulation provides effective cancer therapy. In the present review, we provide a mechanistic discussion of autophagy in prostate cancer. Autophagy can promote/inhibit proliferation and survival of prostate cancer cells. Besides, metastasis of prostate cancer cells is affected (via induction and inhibition) by autophagy. Autophagy can affect the response of prostate cancer cells to therapy such as chemotherapy and radiotherapy, given the close association between autophagy and apoptosis. Increasing evidence has demonstrated that upstream mediators such as AMPK, non-coding RNAs, KLF5, MTOR and others regulate autophagy in prostate cancer. Anti-tumor compounds, for instance phytochemicals, dually inhibit or induce autophagy in prostate cancer therapy. For improving prostate cancer therapy, nanotherapeutics such as chitosan nanoparticles have been developed. With respect to the context-dependent role of autophagy in prostate cancer, genetic tools such as siRNA and CRISPR-Cas9 can be utilized for targeting autophagic genes. Finally, these findings can be translated into preclinical and clinical studies to improve survival and prognosis of prostate cancer patients.

Keywords: Anti-tumor compounds; Autophagy; Biomarker; Non-coding RNAs; Prostate cancer; Therapy response.

Fig. 1

Autophagy and its regulation. The autophagy mechanism has different phases from initiation to elongation and finally, fusion with the lysosome. In each step, various molecular pathways are involved; AMPK, MTOR, and ATGs are the most well-known regulators of autophagy

Fig. 2

The mechanism of autophagy in prostate cancer cell proliferation and survival. Due to the dual role of autophagy, it can both promote and inhibit proliferation and viability of cancer cells. This figure provides a summary of molecular pathways involved in cancer progression regulation by autophagy

Fig. 3

The mechanism of autophagy in prostate cancer metastasis. In addition to proliferation, migration of prostate cancer cells is regulated by autophagy. As shown, upstream mediators can induce EMT-mediated metastasis of prostate cancer cells, and autophagy is capable of suppressing EMT and invasion

Fig. 4

Autophagy regulates the response of prostate cancer cells to therapy. An increasing challenge in prostate cancer therapy is therapy resistance. On the one hand, autophagy activation as a tumor-promoting factor, can inhibit apoptosis and mediate chemoresistance. On the other hand, tumor-suppressor autophagy can sensitize prostate cancer cells to chemotherapy via triggering apoptosis

Fig. 5

MiRNAs, lncRNAs and circRNAs as regulators of autophagy in prostate cancer. As molecular pathways involved in autophagy regulation by non-coding RNAs have been identified, genetic tools can be utilized for affecting the non-coding RNA-autophagy axis in prostate cancer therapy

Fig. 6

Anti-tumor compounds regulate autophagy in prostate cancer therapy. To provide effective prostate cancer therapy, anti-tumor agents (most being phytochemicals) have been developed for affecting autophagy. Various steps of autophagy and its related molecular pathways are modulated by anti-tumor agents in prostate cancer treatment

Fig. 7

The nanotherapeutics and biological vectors in regulating autophagy for prostate cancer therapy

Fig. 8

Other types of autophagy in prostate cancer

Fig. 9

The autophagy mechanism signature in prostate cancer