International Journal of Molecular Sciences

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Dear Colleagues,

Despite therapeutic and diagnostic advancements, prostate cancer (PC) remains the third most prevalent cause of cancer deaths among men in Europe and the second in the United States. Although around 80% of prostate tumors are initially responsive to androgen deprivation therapy (ADT), most patients progress to castration-resistant prostate cancer (CRPC) and metastatic disease. Moreover, androgen receptor (AR) pathway reactivation is complicated by the activation and cross-talk of overlapping cellular survival pathways, such as the phosphoinositide 3-kinase (PI3K)/AKT pathway and its interplay with the mitogen-activated protein kinase (MAPK) and WNT signaling cascades. Thus, molecular targeting of key signaling molecules in prostate cancer remains a clinical challenge.

This Special Issue, entitled “Molecular Research and Treatment of Prostate Cancer”, welcomes original research articles and reviews tackling the mechanistic insights of molecular targeting and the therapeutic potential of combination therapy, as well as investigating the molecular mechanisms of drug failure.

Dr. Manuela Zavatti
Prof. Dr. Sandra Marmiroli
Guest Editors

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Keywords

prostate cancer
PI3K/AKT pathway
resistance mechanism
androgen receptor
MAPK

Published Papers (2 papers)

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Research

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17 pages, 3023 KiB

Open AccessArticle

Overexpression of REST Represses the Epithelial–Mesenchymal Transition Process and Decreases the Aggressiveness of Prostate Cancer Cells

by Sebastián Indo, Octavio Orellana-Serradell, María José Torres, Enrique A. Castellón and Héctor R. Contreras

Int. J. Mol. Sci. 2024, 25(6), 3332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25063332 - 15 Mar 2024

Cited by 1 | Viewed by 599

Abstract

The RE-1 silencing transcription factor (REST) is a repressor factor related to neuroendocrine prostate cancer (PCa) (NEPC), a poor prognostic stage mainly associated with castration-resistant PCa (CRPC). NEPC is associated with cell transdifferentiation and the epithelial–mesenchymal transition (EMT) in cells undergoing androgen deprivation therapy (ADT) and enzalutamide (ENZ). The effect of REST overexpression in the 22rv1 cell line (xenograft-derived prostate cancer) on EMT, migration, invasion, and the viability for ENZ was evaluated. EMT genes, Twist and Zeb1, and the androgen receptor (AR) were evaluated through an RT-qPCR and Western blot in nuclear and cytosolic fractions of REST-overexpressing 22rv1 cells (22rv1-REST). The migratory and invasive capacities of 22rv1-REST cells were evaluated via Transwell^® assays with and without Matrigel, respectively, and their viability for enzalutamide via MTT assays. The 22rv1-REST cells showed decreased nuclear levels of Twist, Zeb1, and AR, and a decreased migration and invasion and a lower viability for ENZ compared to the control. Results were expressed as the mean + SD of three independent experiments (Mann–Whitney U test, Kruskal–Wallis, Tukey test). REST behaves like a tumor suppressor, decreasing the aggressiveness of 22rv1 cells, probably through the repression of EMT and the neuroendocrine phenotype. Furthermore, REST could represent a response marker to ENZ in PCa patients. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Prostate Cancer)

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Review

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21 pages, 1835 KiB

Open AccessReview

Targeting Prostate Cancer, the ‘Tousled Way’

by Siddhant Bhoir and Arrigo De Benedetti

Int. J. Mol. Sci. 2023, 24(13), 11100; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241311100 - 05 Jul 2023

Cited by 1 | Viewed by 1977

Abstract

Androgen deprivation therapy (ADT) has been the mainstay of prostate cancer (PCa) treatment, with success in developing more effective inhibitors of androgen synthesis and antiandrogens in clinical practice. However, hormone deprivation and AR ablation have caused an increase in ADT-insensitive PCas associated with a poor prognosis. Resistance to ADT arises through various mechanisms, and most castration-resistant PCas still rely on the androgen axis, while others become truly androgen receptor (AR)-independent. Our research identified the human tousled-like kinase 1 (TLK1) as a crucial early mediator of PCa cell adaptation to ADT, promoting androgen-independent growth, inhibiting apoptosis, and facilitating cell motility and metastasis. Although explicit, the growing role of TLK1 biology in PCa has remained underrepresented and elusive. In this review, we aim to highlight the diverse functions of TLK1 in PCa, shed light on the molecular mechanisms underlying the transition from androgen-sensitive (AS) to an androgen-insensitive (AI) disease mediated by TLK1, and explore potential strategies to counteract this process. Targeting TLK1 and its associated signaling could prevent PCa progression to the incurable metastatic castration-resistant PCa (mCRPC) stage and provide a promising approach to treating PCa. Full article

(This article belongs to the Special Issue Molecular Research and Treatment of Prostate Cancer)

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