Acidosis Sensing Receptor GPR65 Correlates with Anti-Apoptotic Bcl-2 Family Member Expression in CLL Cells: Potential Implications for the CLL Microenvironment.

Ashley E Rosko Karen S Mccoll

doi:10.4172/2329-6917.1000160

Abstract

The tumor microenvironment is generally an acidic environment, yet the effect of extracellular acidosis on chronic lymphocytic leukemia (CLL) is not well established. Here we are the first to report that the extracellular acid sensing G-protein coupled receptor, GPR65, is expressed in primary CLL cells where its level correlate strongly with anti-apoptotic Bcl-2 family member levels. GPR65 expression is found normally within the lymphoid lineage and has not been previously reported in CLL. We demonstrate a wide range of GPR65 mRNA expression among CLL 87 patient samples. The correlation between GPR65 mRNA levels and Bcl-2 mRNA levels is particularly strong (r=0.8063, p= <0.001). The correlation extends to other anti-apoptotic Bcl-2 family members, Mcl-1 (r=0.4847, p=0.0010) and Bcl-xl (r=0.3411, p=0.0252), although at lower levels of significance. No correlation is detected between GPR65 and levels of the pro-apoptotic proteins BIM, PUMA or NOXA. GPR65 expression also correlates with the favorable prognostic marker of 13q deletion. The present findings suggest the acid sensing receptor GPR65 may be of significance to allow CLL tolerance of extracellular acidosis. The correlation of GPR65 with Bcl-2 suggests a novel cytoprotective mechanism that enables CLL cell adaptation to acidic extracellular conditions. These findings suggest the potential value of targeting GPR65 therapeutically.

Highlights

Among the adaptive hallmarks of cancer cells is the ability to survive and proliferate within a caustic tumor microenvironment [1]
We find that levels of GPR65 in chronic lymphocytic leukemia (CLL) cells are not altered by extracellular acidosis, but average levels of Bcl-2 mRNA increase in response to reduced extracellular pH (Figure 3)
The major findings of this study are that the extracellular acidosis sensing receptor, GPR65, is expressed in primary human CLL cells and that its expression levels correlate strongly with expression levels of the anti-apoptotic protein Bcl-2

Summary

Introduction

Among the adaptive hallmarks of cancer cells is the ability to survive and proliferate within a caustic tumor microenvironment [1]. The upregulation of glycolysis, generating lactic acid paired with an increase in proton efflux, results in an abundance of acidic waste products within the extracellular space [4,5,6]. The culmination of this metabolic stress along with decreased clearance of metabolic waste products lends itself to an acidic extracellular environment [7,8]. Acidosis has been detected in the tumor microenvironment by various methods utilizing microelectrodes or non-invasive imaging approaches, documenting a spectrum of acidic conditions that vary with each malignancy [12,13,14]

Methods

Results

Conclusion