Effect of the silencing of CA12 and of the activation of NF-kB pathway TNFa in glioblastoma stem cell

Abstract

The treatment of glioblastoma (GBM) remains a major challenge for clinicians since these highly aggressive brain tumors are highly resistant to radio- and chemotherapy, and recurrence is practically inevitable. The poor prognosis of GBM patients is in part due to the presence of a heterogeneous population of glioblastoma stem cells (GSCs) within the tumor, characterized by invasive behavior and resistance to apoptosis. Hypoxia is a predominant feature in the microenvironment of GBM and is associated with tumor growth. GBM cells express membrane-bound carbonic anhydrases (CAs), a family of ubiquitous enzymes that regulate many physiological and pathological processes. These enzymes have been shown to regulate environmental acidity and could be particularly relevant to understand mechanisms of glioma stem cell invasion and propagation. In particular, the expression of CA12 in GSCs may directly promote the survival and proliferation of disseminated cancer cells in a hypoxic environment. The current proposal will investigate the mechanisms of CA12 that may underlie glioma progression. In the first stage of this research, conducted in Brazil, we evaluated the effects of inhibiting CA12 with indisulam in vivo and in vitro. Our results showed that indisulam reduced cell proliferation, increased apoptosis, reduced tumor volume, and potentiated the effect of the standard chemotherapeutic temozolomide. For the second stage of research, we propose to determine the potential correlation of CA12 expression with molecular subtype of glioblastoma and study the effects of CA12 knockdown on GSC growth, chemoresistance, invasion and and angiogenesis using orthotopic xenograft models. We believe that our results will contribute significantly to understanding the mechanisms of action of carbonic anhydrases in the glioma microenvironment, fostering new therapeutic approaches. (AU)