Introduction: Gap junction protein Connexin 43 (Cx43) appears to confer resistance of glioblastomas to Temozolomide (TMZ)- particularly in tumors that recur after initially responding to therapy. Tumor recurrence is felt to be predicated on surviving glioblastoma stem cells. We sought to confirm the relationship of CX43 expression in glioblastoma cells and their resistance to TMZ. We also sought to study CX43 expression in glioblastoma stem cells and their resistance to TMZ.

Methods: Fresh glioblastoma specimens were obtained from a series of patients undergoing surgery at our institution. TMZ resistant Glioblastoma cell lines were cultured as were derivative stem cells (GSCs), and were studied with respect to prominence of CX43. Mice were inoculated with tumor and GSCs. Cell viability in culture and in inoculated mice was then evaluated after exposure to TMZ.

Results: CX43 expression correlated directly with TMZ resistance both in culture and in inoculated mice. Glioblastoma stem cells exhibited higher expression of CX43 and greater TMZ resistance.

Conclusions: CX43 expression is thought to confer resistance of glioblastoma cells to Temozolomide therapy. This study supported this contention showing an inverse relationship of CX43 to tumor cell sensitivity. We demonstrated high levels of expression of CX43 in glioblastoma stem cells. This correlated with greater TMZ resistance. This supports the contention that glioblastoma recurrence may be predicated upon surviving stem cells and that the stem cell resistance to TMZ may be conferred by greater expression of CX43. Thus inhibition of CX43 may offer a therapeutic target to increase TMZ sensitivity in glioblastomas.

Patient Care: the study will lead to better understanding of glioblastoma recurrence and temozolomide resistance, and may suggest novel approaches to therapy.

Learning Objectives: to learn mechanisms of glioblastoma resistance to temozolomide to learn about role of glioblastoma stem cells in temozolomide resistance and recurrence

References: Yan, K., Yang, K., and Rich, J. N. (2013) The evolving landscape of glioblastoma stem cells. Current opinion in neurology 26, 701-707 Enhanced MGMT expression contributes to temozolomide resistance in glioma stem-like cells. Chinese journal of cancer 33, 115-122 Gielen, P. R., Aftab, Q., Ma, N., Chen, V. C., Hong, X., Lozinsky, S., Naus, C. C., and Sin, W. C. (2013) Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway. Neuropharmacology 75, 539-548