Regulatory Mechanisms of STAT3 in GBM and its Impact on TMZ Resistance

Abstract

STAT3, a key member of the Signal Transducer and Activator of Transcription (STAT) family, plays a vital role in the development and progression of glioblastoma (GBM), as well as in the resistance to the chemotherapy drug temozolomide (TMZ). This review outlines the dysregulation of STAT3 in GBM, focusing on its activation mechanisms and its contribution to TMZ resistance. STAT3 can be activated by cytokines, like IL-6, growth factors, and membrane receptors, like EGFR. In GBM, constitutively active STAT3 enhances tumor growth and therapy resistance. Specifically, resistance to TMZ, a standard chemotherapeutic agent for GBM, is facilitated by STAT3-induced expression of the DNA repair enzyme O6-methylguanine-DNA methyltransferase and anti-apoptotic proteins like Bcl-2, as well as through the regulation of microRNAs. To combat TMZ resistance in GBM, strategies that inhibit STAT3 activity have been explored. Recent advancements, such as the use of small molecule inhibitors targeting STAT3 and its upstream or downstream regulators, RNA-based therapies, as well as the development of nanocarriers for targeted delivery of STAT3-targeting small interfering RNA across the blood-brain barrier, have demonstrated significant potential in enhancing the sensitivity of GBM to TMZ. These targeted therapies hold promise for improving the treatment outcomes of patients with GBM.