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. Graphical abstract

Combination of the NRF2 Inhibitor and Autophagy Inhibitor Significantly Inhibited Tumorigenicity of Castration-Resistant Prostate Cancer

“…These results further indicated that NRF2 may serve different roles in the progression of PCa and was activated during PCa androgen-independent transformation. Despite that no autophagy-targeting drugs were approved for PCa therapy, several preclinical studies indicated the promising progression about the using of autophagy-related drugs in PCa [ 25 – 27 ]. For example, diosgenin has high antitumor activity in prostate cancer via inducing autophagy [ 26 ].…”

Identification of Autophagy-Related LncRNA to Predict the Prognosis of Colorectal Cancer

“…Autophagy, a programmed cellular process, mainly contributes to the degradation and recycling of damaged cellular organelles and macromolecules ( Kimmelman and White, 2017 ; Li et al, 2020 ; Ashrafizadeh et al, 2022 ). Dysfunction of the autophagic process has been associated with the onset and development of many human chronic pathologies, such as cardiovascular, metabolic, and neurodegenerative diseases as well as cancer ( Francesca et al, 2018 ).…”

Exploring the relationship between autophagy and Gefitinib resistance in NSCLC by silencing PDLIM5 using ultrasound-targeted microbubble destruction technology

“…The role of autophagy in tumour development and its role in anti-tumour drug functionality are current popular topics of research. While, the role of autophagy in cancer is controversial and no consensus has been reached regarding the precise involvement of autophagy in cancer progression and inhibition [ 5 ]. When autophagy exerts a pro-survival role, its stimulation results in a decrease in apoptosis of cancer cells, paving the way for cancer progression [ 6 ].…”

“…When autophagy exerts a pro-survival role, its stimulation results in a decrease in apoptosis of cancer cells, paving the way for cancer progression [ 6 ]. However, when autophagy possesses an anti-tumor role, its activation significantly enhances sensitivity of cancer cells to therapy [ 5 ]. In primary lung tumors, autophagy associated with drug resistance has been reported as a biomarker for subclassification, differentiation, and local metastasis [ 7 ].…”

“…Clinical studies have shown that the inhibition of autophagy enhances the resistance of gastric cancer [ 15 ], prostate cancer [ 16 ], ovarian carcinoma [ 17 ], hepatocellular carcinoma [ 18 ], colorectal cancer [ 14 ] and osteosarcoma [ 19 ] to chemotherapy. Conversely,, literature also reports that the activation of autophagy enhances the sensitivity of tumour cells to drugs or activation of the autophagy signalling pathway increases the level of autophagy to improve drug sensitivity via promoting apoptosis [ 5 ]. Similarly, there is also evidence demonstrating that autophagy induction participates in elevated efficacy of chemotherapy in cancer elimination [ 20 – 22 ].…”