HOXA10 is associated with temozolomide resistance through regulation of the homologous recombinant DNA repair pathway in glioblastoma cell lines.

Jin Wook Kim,Seung-Ki Kim,Chul-Kee Park,Ja Eun Kim,Ji Young Kim,Hyun-Tai Chung

doi:10.18632/genesandcancer.16

Abstract

Temozolomide resistance is associated with multiple DNA repair pathways. We investigated homeobox (HOX) genes for their role in temozolomide resistance, focusing on the homologous recombination (HR) pathway, and we tested their therapeutic implications in conjunction with O(6)-methylguanine DNA methyltransferase (MGMT) status. Two glioblastoma cell lines with different MGMT statuses were used to test the augmented anticancer effect of temozolomide with HOXA10 inhibition. In vitro experiments, including gene expression studies with RNA interference, were performed to verify the related pathway dynamics. HOXA10 inhibition reinforced temozolomide sensitivity independent of MGMT status and was related to the impaired double-strand DNA breakage repair process resulting from the downregulation of Rad51 paralogs. Early growth response 1 (EGR1) and phosphatase and tensin homolog (PTEN) were the regulatory mediators between HOXA10 and the HR pathway. Moreover, HOXA10 inhibition selectively affected the nuclear function of PTEN without interfering with its cytoplasmic function of suppressing the phosphoinositide 3-kinase/Akt pathway. The mechanism of HR pathway regulation by HOXA10 harbors another target mechanism for overcoming temozolomide resistance in glioblastoma patients.

Highlights

Temozolomide has been a mainstay of chemotherapy for glioblastoma (GBM) for the past decade but still produces unsatisfactory clinical outcomes
We investigated the mechanism of HOXA10 regarding its role in temozolomide resistance using glioblastoma cell lines and tested the therapeutic implication of temozolomide resistance in conjunction with methylguanine DNA methyltransferase (MGMT) status
After knockdown with iHOXA10, RT-PCR data showed significant suppression of Early growth response 1 (EGR1) and phosphatase and tensin homolog (PTEN). In both LN18 (93% and 30% suppression) and LN229 (25% and 58% suppression) cells (Figure 2A). These results suggested that EGR1 and PTEN are the mediators regulated by HOXA10 status

Summary

INTRODUCTION

Temozolomide has been a mainstay of chemotherapy for glioblastoma (GBM) for the past decade but still produces unsatisfactory clinical outcomes. Unrepaired O6- methylguanine successively results in thymine mispairing during DNA replication, and these mispairs result in futile cycles of the repair process by the MMR system due to the persistence of O6-methylguanine in the template strand [5] These futile cycles of the DNA repair process eventually cause double-strand DNA breaks, leading to cell apoptosis if www.impactjournals.com/Genes & Cancer the HR system functions inadequately [5]. Solid evidence exists concerning the role of HOX genes in oncogenesis and therapeutic resistance in gliomas, the exact mechanism remains unclear, and only a small number of recent studies have been published [9, 10, 18]. The result of the present study suggests a possible hypothesis for the temozolomide non-responders in MGMT-inactive GBM patients

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS