Abstract
It was reported that MGMTlow gliomas may still be resistant to TMZ, while the mechanisms remain poorly understood. In this study, we demonstrated that rho-associated kinase 2 (ROCK2), a cytoskeleton regulator, was highly expressed in MGMTlow recurrent gliomas, and its expression strongly correlated with poor overall survival (OS) time in a subset of MGMTlow recurrent gliomas patients with TMZ therapy. And we also found that overactive ROCK2 enhanced homologous recombination repair (HR) in TMZ-resistant (TMZ-R) glioma cell lines with low MGMT expression. Silencing ROCK2 impaired HR repair, and induced double-strand break (DSB) and eradicated TMZ-R glioma cells in culture. Notably, in MGMTlow TMZ-R models, as a key factor of HR, ataxia telangiectasia-mutated (ATM) expression was upregulated directly by hyper-activation of ROCK2 to improve HR efficiency. ROCK2 enhanced the binding of transcription factor zinc finger E-box binding homeobox 1 (ZEB1) to ATM promoter for increasing ATM expression. Moreover, ROCK2 transformed ZEB1 into a gene activator via Yes-associated protein 1 (YAP1). These results provide evidence for the use of ROCK inhibitors in the clinical therapy for MGMTlow TMZ-resistant glioma. Our study also offered novel insights for improving therapeutic management of MGMTlow gliomas.
Highlights
Resistance to temozolomide (TMZ) therapy is a major cause of glioma treatment failure, and overcoming its resistance is critical to improving treatment outcomes
These findings demonstrated a strong correlation between rho-associated kinase 2 (ROCK2) and TMZ response in MGMTlow recurrent glioma patients and might suggest a potential role of ROCK2 on TMZ-R
In a separate project in our laboratory, we determined a role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells, and we revealed that ROCK2 induced increasement of zinc finger E-box binding homeobox 1 (ZEB1) expression and enhancement of DNA repair system [28]
Summary
Resistance to temozolomide (TMZ) therapy is a major cause of glioma treatment failure, and overcoming its resistance is critical to improving treatment outcomes. The demethylating enzyme O6-methylguanine-DNA methyltransferase (MGMT) has been implicated in intrinsic TMZ-resistance (TMZ-R) and recurrence by removing alkyl groups from the O6 position of guanine directly [1]. With low MGMT level, TMZ-R gliomas exhibited a gene mutation [5]. Recurrent gliomas exhibited transcriptional silencing of the MGMT gene, followed by dysfunction of the mismatch repair (MMR) system [6] and hyperfunction of the DNA repair system [7]. With deficiency of MMR, DNA damage repair (DDR) systems were activated, leading to TMZ-R [8, 9]. The functional availability of the DDR system presumably regulates the response of recurrent gliomas to TMZ. We hypothesize that DDR signaling is enhanced in TMZ-R glioma cells, which contributes to their phenotypic resistance
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