Mechanisms underlying prostate cancer sensitivity to reactive oxygen species: overcoming radiotherapy resistance and recent clinical advances

Sep 23, 2026

Uploaded by Stanley

Prostate cancer (PCa) is a leading cause of cancer-related mortality among men, and radiotherapy remains central to PCa management but is limited by emerging resistance. Reactive oxygen species (ROS) generated by radiation both drive DNA damage and apoptosis and also support tumor progression and radioresistance. Elevated ROS promotes metabolic reprogramming, oncogenic signaling, and tumor microenvironment changes, including immune modulation and EMT. Key pathways such as Nrf2/Keap1, Bcl-2 mutations, Speckle-type POZ protein alterations, and links involving hypoxia, AR-V variants, and ferroptosis regulators are reviewed, aiming to guide targeted radiosensitization.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Introduction

Radiotherapy and ROS in PCa

ADT and combined treatment challenges

Radiation delivery approaches (EBRT, SBRT, IMRT)

Cancer Biol Med 2025. doi: 10.20892/j.issn.2095-3941.2024.0584 REVIEW Mechanisms underlying prostate cancer sensitivity to reactive oxygen species: overcoming radiotherapy resistance and recent clinical advances Meidan Wang1*, Rui Xing2*, Liqun Wang1*, Mingyue Pan3, Ruoyun Zhang4, Ting Li5, Weiqiang Sun6, Jing Zhou7 1 Department of Radiation Oncology, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany; 2 Department of Hematology, Dongyang Hospital Affiliated to Wenzhou Medical University, Dongyang People’s Hospital, Dongyang 322100, China; 3 Faculty of Law, University of Freiburg, Freiburg 79085, Germany; 4School of Chinese Language and Literature, Tangshan Normal University, Tangshan 063000, China; 5 Department of Oncology, Shandong Provincial Third Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, China; 6 Department of Hepatobiliary Surgery, General Surgery, Jinan Third People’s Hospital, Jinan 250031, China; 7 Department of Chemoradiotherapy, Ningbo NO. 2 Hospital, Ningbo 315010, China | ABSTRACT | Prostate cancer (PCa) is a leading cause of cancer-related mortality among men. Radiotherapy is the cornerstone of PCa treatment. However, a major limitation of radiotherapy is the development of resistance, which compromises treatment efficacy. Reactive oxygen species (ROS), which are generated by radiation, have a dual role in PCa by inducing DNA damage and apoptosis, while also promoting tumor progression and radioresistance. Elevated ROS levels enhance metabolic reprogramming, activate oncogenic pathways, and influence the tumor microenvironment by modulating immune responses and promoting the epithelial-mesenchymal transition (EMT) . Key molecular mechanisms, including the Nrf2/Keap1 signaling axis, Bcl-2 mutations, and Speckle-type POZ protein alterations, contribute to radioresistance by enhancing antioxidant defenses and DNA repair capacity. Additionally, the interplay between hypoxia, androgen receptor variants (AR-Vs), and ferroptosis regulators further influence radiotherapy outcomes. Understanding these resistance mechanisms is crucial for developing targeted strategies to enhance radiosensitivity and improve therapeutic outcomes in PCa patients. | | --- | --- | | KEYWORDS | Prostate cancer (PCa); radiation therapy (RT); reactive oxygen species (ROS); radiotherapy resistance; antioxidants | Introduction Prostate cancer (PCa) detection and management have improved since the introduction of prostate-specific antigen (PSA) testing in the early 1990s. Nevertheless, PCa remains the second leading cause of cancer-related mortality in men in the United States with an estimated 299,010 new cases and 35,250 deaths projected in 20241. Racial disparities persist because Black patients have nearly twice the lifetime *These authors contributed equally to this work. Correspondence to: Jing Zhou E-mail: [zhoujing0077@outlook.com](zhoujing0077@outlook.com) ORCID ID: [https://orcid.org/0009-0008-2746-2199](https://orcid.org/0009-0008-2746-2199) Received December 12, 2024; accepted May 26, 2025; published online July 10, 2025. Available [at www.cancerbiomed.org](at www.cancerbiomed.org) ©2025 The Authors. Creative Commons Attribution-NonCommercial 4.0 International License risk of PCa-related deaths compared to non-Hispanic White patients, in part due to differences in access to care and disease biology2. Androgen deprivation therapy (ADT) is the cornerstone of PCa treatment, particularly in combination with radiotherapy for intermediate- and high-risk localized PCa3,4 . However, challenges remain, including uncertainty regarding the optimal use and duration of ADT following radical prostatectomy5. In addition, combination therapies increase toxicity and raise concerns about the development of drug resistance with prolonged use, underscoring the need for continued monitoring and novel strategies to mitigate resistance6. Radiation therapy is a critical component of

FAQs

Why does radiotherapy resistance reduce treatment efficacy in prostate cancer?

Radiotherapy can induce ROS-mediated DNA damage and apoptosis, but resistant tumors survive by counteracting oxidative stress and activating survival programs, ultimately undermining treatment effectiveness.

How do reactive oxygen species (ROS) influence both tumor killing and radioresistance?

ROS generated by radiation can trigger DNA damage and apoptosis, yet elevated ROS levels can also promote metabolic reprogramming, activate oncogenic pathways, and reshape the tumor microenvironment to support progression and radioresistance.

Which molecular and microenvironment factors are highlighted as drivers of radioresistance?

The review emphasizes mechanisms including the Nrf2/Keap1 signaling axis, Bcl-2 mutations, Speckle-type POZ protein alterations, and interactions among hypoxia, androgen receptor variants (AR-Vs), and ferroptosis regulators.

Sep 23, 2026

Uploaded by Stanley