Cell-penetrating peptides based on Connexin43 as potential therapies against malignant brain tumors
Institute of Neuroscience Castilla y Leon (INCYL) University of Salamanca, Spain
Although the relationship between Connexin and cancer was first described more than 50 years ago, the interest in this protein is increasing for the development of cancer therapies. Connexin43 (Cx43), the major protein forming gap junctions in astrocytes, is down-regulated in several tumors, including high-grade gliomas. Restoring Cx43 expression in these tumoral cells inhibits oncogenic activity of c-Src with the subsequent reduction in proliferation. The inhibition of c-Src is caused by a short region of Cx43, amino acids 266 to 283, that recruits c-Src, together with its inhibitors CSK and PTEN. Importantly, in addition to the beneficial effects caused by Src inhibition, Cx43 can also have detrimental effects because of the increase heterologous junctional coupling. Consequently, we proposed to restore just the region of Cx43 responsible for c-Src inhibition, instead of the whole protein, in glioma cells. To do so, we design a cell-penetrating peptide, containing the region of Cx43 that expands from amino acid 266 to 283 fused to the TAT penetrating sequence (TAT-Cx43266-283). Our results revealed that TAT-Cx43266-283 inhibited c-Src activity in a broad spectrum of glioma cells, including primary glioma stem cells obtained from patients. The oncoprotein c-Src y is required to maintain stemness, proliferation, migration and invasion in cancer stem cells. Not surprisingly, TAT-Cx43266-283, by inhibiting c-Src, reduced the expression of important markers of stemness, the formation of neurospheres, proliferation, survival, migration and invasion in GSCs, including freshly removed surgical specimens handled as undissociated glioblastoma blocks in culture. Our last studies showed that TAT-Cx43266-283 strongly reduced malignant growth in mouse models of glioma in vivo and suggested an active participation of the glioma microenvironment in the anti-tumor effect. Altogether, these data indicate the relevance of TAT-Cx43266-283 as a potential therapy against malignant gliomas.
Host: Amanda Sierra