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. 2006 Apr 5;10(2):223–234. doi: 10.1111/j.1750-3639.2000.tb00256.x

Bag‐1 and Bcl‐2 Gene Transfer in Malignant Glioma: Modulation of Cell Cycle Regulation and Apoptosis

Wilfried Roth 1, Cornelia Grimmel 1, Lorenz Rieger 1, Herwig Strik 2, Shinichi Takayama 3, Stanislaw Krajewski 3, Richard Meyermann 2, Johannes Dichgans 1, John C Reed 3, Michael Weller 1,✉
PMCID: PMC8098428  PMID: 10764042

Abstract

Bag‐1 is a heat shock 70 kDa (Hsp70)‐binding protein that can collaborate with Bcl‐2 in suppressing apoptosis under some conditions. Here, we report that 11 of 12 human glioma cell lines express Bag‐1 protein in vitro. Moreover, 15 of 19 human glioblastomas expressed Bag‐1 as assessed by immunohistochemistry in primary tumor specimens. To examine the biological effects of Bag‐1 in glioma cells, we expressed Bag‐1 or Bcl‐2 transgenes in 2 human malignant glioma cell lines, LN‐18 and LN‐229. Bag‐1 significantly slowed glioma cell growth and reduced clonogenicity of both cell lines in vitro. Coexpressed Bcl‐2 abrogated these effects of Bag‐1. Intracranial LN‐229 glioma xenografts implanted into nude mice revealed a substantial growth advantage afforded by Bcl‐2. Bag‐1 had no such effect, either in the absence or presence of Bcl‐2. Upon serum starvation in vitro, Bcl‐2 prevented cell death whereas Bag‐1 did not. Both Bcl‐2 and Bag‐1 slowed proliferation of serum‐starved cells when expressed alone. Importantly, coexpression of Bcl‐2 and Bag‐1 provided a distinct growth advantage under conditions of serum starvation that is probably the result of (i) the death‐preventing activity of Bcl‐2 and (ii) the property of Bag‐1 to overcome a Bcl‐2‐mediated enhancement of exit from the cell cycle. In contrast to these Bcl‐2/Bag‐1 interactions observed under serum starvation conditions, Bag‐1 did not further enhance the strong protection from staurosporine‐, CD95 (Fas/Apo1) ligand‐, Apo2 ligand (TRAIL)‐ or chemotherapeutic drug‐induced apoptosis afforded by Bcl‐2. Taken together, these results indicate a role for Bag‐1/Bcl‐2 interactions in providing a survival advantage to cancer cells in a deprived microenvironment that may be characteristic of ischemic/hypoxic tumors such as human glioblastoma multiforme, and suggest that Bcl‐2/Bag‐1 interactions also modulate cell proliferation.

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