Abstract
Malignant gliomas are devastating neoplasia with limited curative treatment options. Temozolomide (TMZ, Temcat®, Temodal® or Temodar®) is a first-line treatment for malignant gliomas but the development of drug resistance remains a major concern. Activating transcription factor 4 (ATF4) is a critical oxido-metabolic regulator in gliomas, and its role in the pathogenesis of TMZ-resistance remains elusive. We investigated the effect of TMZ on human glioma cells under conditions of enhanced ATF4 expression (ATF4OE) and ATF4 knock down (ATF4KD). We monitored cell survival, ATF4 mRNA expression of ATF4 and xCT (SLC7a11) regulation within human gliomas. TMZ treatment induces a transcriptional response with elevated expression of ATF4, xCT and Nrf2, as a sign of ER stress and toxic cell damage response. ATF4 overexpression (ATF4OE) fosters TMZ resistance in human gliomas and inhibits TMZ-induced autophagy. Conversely, ATF4 suppression by small interfering RNAs (ATF4KD) leads to increased TMZ susceptibility and autophagy in comparison to wild type gliomas. ATF4OE gliomas show reduced cell cycle shift and apoptotic cell death, whereas ATF4KD gliomas reveal higher susceptibility towards cell cycle rearrangements. Hence, the migration capacity of ATF4OE glioma cells is almost not affected by TMZ treatment. In contrast, ATF4KD gliomas show a migratory stop following TMZ application. Mechanistically, xCT elevation is a consequence of ATF4 activation and increased levels of xCT amplifies ATF4-induced TMZ resistance. Our data show that ATF4 operates as a chemo-resistance gene in gliomas, and the tumor promoting function of ATF4 is mainly determined by its transcriptional target xCT. Therefore, therapeutic inactivation of ATF4 can be a promising strategy to overcome chemo-resistance and promote drug efficacy in human gliomas.
Highlights
Malignant gliomas are the most lethal primary brain tumors in children and adults [1]
We investigated the effect of TMZ on human glioma cells under conditions of enhanced Activating transcription factor 4 (ATF4) expression (ATF4OE) and ATF4 knock down (ATF4KD)
Immunoblot analyses revealed that both human glioma cell lines U87 and U251 show increased ATF4 protein levels compared to non-transformed primary astrocytes (Figure 1A)
Summary
Malignant gliomas (abbreviated as gliomas) are the most lethal primary brain tumors in children and adults [1]. Recent advances in neurooncology uncovered cytotoxic features of malignant gliomas impacting on brain cell viability. These processes can affect brain functioning and thereby exacerbating the space occupying effects and neurological deficits and [10]. The current standard-of-care for GBM patients includes adjuvant temozolomide (TMZ) treatment as part of the current multimodal approach. This www.impactjournals.com/oncotarget treatment strategy is currently the best clinical practice, conferring still a median survival time of only 14.6 months compared with 12.2 months for patients receiving only radiotherapy [5]. Temozolomide (TMZ brand names Temodal® in Europe and Temcad® in the USA) offers some hope to GBM patients with increasing progression free and overall survival of few months, a best 5 year survival rate of only 9.8% is currently achieved [1]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
