Replication Protein A (RPA) Mediates Radio-Resistance of Glioblastoma Cancer Stem-Like Cells

Abstract

Glioblastoma (GBM) is among the deadliest of solid tumors with median survival rates of approximately 12–15 months despite maximal therapeutic intervention. A rare population of self-renewing cells referred to as GBM cancer stem-like cells (GSCs) are believed to be the source of inevitable recurrence in GBM. GSCs exhibit preferential activation of the DNA damage response pathway (DDR) and evade ionizing radiation (IR) therapy by superior execution of DNA repair compared to their differentiated counterparts, differentiated GBM cells (DGCs). Replication Protein A (RPA) plays a central role in most of the DNA metabolic processes essential for genomic stability, including DNA repair. Here, we show that RPA is preferentially expressed by GSCs and high RPA expression informs poor glioma patient survival. RPA loss either by shRNA-mediated silencing or chemical inhibition impairs GSCs’ survival and self-renewal and most importantly, sensitizes these cells to IR. This newly uncovered role of RPA in GSCs supports its potential clinical significance as a druggable biomarker in GBM.

Replication protein A: a multifunctional protein with roles in DNA replication, repair and beyond

“…Consequently, HAMNO elevates DNA replication stress and mitigates tumor growth ( 350 ). A recent report demonstrates that HAMNO sensitizes glioblastoma cancer stem-like cells to ionizing radiation ( 351 ). The potential of other RPA inhibitors ( 352–356 ) as cancer therapeutics or as chemosensitizing agents needs to be validated.…”

Harnessing the targeting potential of differential radiobiological effects of photon versus particle radiation for cancer treatment

“…Replication protein A1 (RPA1) is a heterotrimeric ssDNA‐binding protein that participates in DNA replication and is required for each of the three major DNA repair pathways: NER, BER, and DSBs repair. It is found that RPA loss either by shRNA‐mediated silencing or chemical inhibition (HAMNO) impairs the survival and self‐renewing potential of GSCs (glioblastoma cancer stem‐like cells) while increasing their sensitivity to IR by impairing the DNA repair capacity of GSCs (Pedersen, Anne, Elbaek, Vitting‐Serup, & Hamerlik, 2020). Depletion of RPA1 increases CNE‐2R (human radioresistant nasopharyngeal carcinoma cell line) and TE‐1 R (radioresistant oesophageal cancer cells) cell radio‐sensitivity to X‐rays by impairing Rad51 recruitment to damage sites, contributing to G2/M phase arrest (Di, Sanyuan, Hong & Dahai, 2014; Z. Zhang et al, 2018).…”

BET degrader inhibits tumor progression and stem-like cell growth via Wnt/β-catenin signaling repression in glioma cells

“…The success of therapy can be thwarted by features of cancer stem cells (CSCs) such as self-renewal and maintenance of tumor characteristics 47 . The presence of CSCs in glioma has been pointed out, which can help design and test new therapies for glioma 48,49 . Despite surgery and chemotherapy, 70% of patients are resistant to chemotherapy This resistance can be traced back to the CSCs, and the relevant research required this aspect to be kept in mind when designing new strategies 50 .…”