Virtual Seminar: Src Inhibitory Peptides Based on Connexin43 as a Promising Therapy Against Glioblastoma

About this Seminar

Glioblastomas are the most frequent primary brain tumors and remain among the most incurable cancers. Connexin43 (Cx43), the main constituent of gap junctions, has been traditionally considered a tumor suppressor protein in glioblastoma; however, Cx43 can also play pro-tumorigenic roles, suggesting that very specific tools should be used to mimic specifically the antitumor effects of Cx43. The C-terminal domain of Cx43 interacts with a plethora of molecules and acts as an intracellular signaling hub. This is the case for the proto-oncoprotein c-Src, which is recruited by Cx43 together with its inhibitors CSK and PTEN. This interaction causes the inhibition of c-Src and its downstream oncogenic pathways. Based on this inhibitory mechanism, Dr. Tabernero and her lab designed a cell-penetrating peptide, TAT-Cx43_266-283, that recapitulates the inhibition of c-Src by Cx43. Malignant gliomas have high oncogenic c-Src activity; moreover, cancer stem cells, including glioblastoma stem cells (GSCs), rely on the activity of this oncoprotein for metabolic reprogramming, survival, stemness, and invasion. Importantly, TAT-Cx43_266-283 inhibits c-Src activity and consequently exerts potent antitumor effects specifically in glioblastoma cells without affecting healthy brain cells, such as neurons and astrocytes. Interestingly, Tabernero's studies suggest that the mechanism of the antitumor action of TAT-Cx43_266-283 involves inhibition of the oncogenic activity of c-Src and not blockade of endogenous Cx43 function. Indeed, the level of Cx43 protein expression is very low and the activity of c-Src is high in TAT-Cx43_266-283-targeted cells, such as GSCs, while no effect of TAT-Cx43_266-283 on cell viability is found in cells with high expression of Cx43 protein and low activity of c-Src, such as astrocytes. In brief, Tabernero found that TAT-Cx43_266-283 reduces migration, invasion, metabolic plasticity and survival in mice and human GSCs, including freshly removed surgical specimens studied as undissociated glioblastoma blocks. Moreover, TAT-Cx43_266-283 inhibits c-Src, impairs malignant growth, and enhances survival in mouse models in vivo, without exerting toxicity in endogenous brain cells, supporting the translational potential of this peptide for the treatment of glioblastoma.

Additional Details

This is a free event hosted by the Fralin Biomedical Research Institute and co-sponsored by the institute's Cancer Research Group. The Pioneers in Biomedical Research Seminar Series, which runs annually from September to May, has featured leading biomedical researchers from throughout the country since the program began in 2012. The lectures are also open to all members of the Virginia Tech community including graduate students, undergraduates, faculty, and staff, as well as the public.

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