Gliomas are tumors of glial cell origin, with glioblastoma multiforme being one of the most aggressive forms of brain cancer. Unlike normal glia, glioma cells express low levels of functional connexin (Cx) hemichannel/gap junction protein and high levels of polyamines (PA). A lot of attention in the anti-cancer strategies focuses on either (i) PA or (ii) Cxs, although there is not very much known about how PA and Cx hemichannels/gap- junctions co-interact. Expression of Cx in glioma cells is found predominantly in the cytoplasm with very little cell surface expression. In spite of this, there is still highly functional gap junctional intercellular communication between glioma cells. It is unclear how low levels of cell surface Cx expression allow such high gap junctional intercellular communication between glioma cells. Our preliminary data indicate that (1) PA eliminate cationic block of Cx43 gap junctions/hemichannels and (2) increase their open probability. Based on these findings, we hypothesize that high levels of PA present in glioma cells potentiate Cx43 channel opening and enhance gap junctional intercellular communication. As a result, propagation of the intercellular signals through Cx43 gap junctions/hemichannels will be elevated. On the other hand, it was recently shown that intracellular PA block Cx40 gap junctions demonstrating a different effect of PA on different types of Cxs. Currently, there is no data about PA and Cxs (other than Cx43) in glial cells. The present study will examine the interaction between polyamines and Cx hemichannels/gap junctions in normal and malignant glia. To test our hypothesis we propose the following specific aims:
Specific Aim 1 : To determine the polyamine dependence of connexin hemichannel currents and gap junction communication in astrocytes, Cxs transfected cells and Cx43 conditional knock-out mice.
Specific Aim 2 : To determine how different types of Cxs overexpressed in glioma cells participate in gap junction intercellular communication and may contribute during cancer treatment. Significance: The results of these studies will provide a link between two targets of anti-cancer therapy;connexins and polyamines. We will define the effects polyamines on the different Cxs. This knowledge will help us to develop an effective strategy to treat cancer cells when the levels of PA are elevated. By regulation of Cxs, we can modulate gap junctional intercellular communication between glioma cells and potentially communication between glioma cells and the normal astrocytes in the tumor microenvironment.
The results of these studies will provide a link between two targets of anti-cancer therapy;connexins and polyamines. We will define the effects polyamines on the different Cxs. This knowledge will help us to develop an effective strategy to treat cancer cells when the levels of PA are elevated. By regulation of Cxs, we can modulate gap junctional intercellular communication between glioma cells and potentially communication between glioma cells and the normal astrocytes in the tumor microenvironment.
