Impact of acidosis on ζ-crystallin-mediated bcl-2 expression in leukemic cells

The human antiapoptotic bcl-2 gene is over-expressed in various malignancies, including leukemias/lymphomas. Its post-transcriptional regulation is orchestrated by an adenine-uracil rich element (AU-Rich Element, ARE) lying in the 3’-UTR of bcl-2 mRNA which interacts with numerous ARE-binding proteins (AUBPs) in modulating mRNA stability or translation. In 2010, we identified a new bcl-2 mRNA stabilizing AUBP, namely ζ-crystallin, and demonstrated that it contributed to the over-expression of bcl-2 in acute lymphatic leukemia (ALL) cells as a result of its increased binding to the bcl-2 ARE in T cells of ALL patients compared to normal T lymphocytes. Moreover, ζ-crystallin has been previously demonstrated to bind to specific AU-Rich RNA sequences, called pH-response element (pH-RE), lying in the 3’-UTR of some mRNAs whose genes code for proteins involved in the physiological maintenance of acid-base balance in renal cells. Acidosis, mainly consequent to the “Warburg effect”, is a biochemical hallmark of the tumour microenvironment. Associating the above evidences with the recent report that acidosis increased the level of some antiapoptotic proteins, included Bcl-2, by a mechanism involving the acid-sensing G protein-coupled receptor (TDGA8), prompted us to hypothesize that the direct actor of bcl-2 overexpression in acidosis is ζ-crystallin. Here, we report by which mechanisms acute acidosis impacts on ζ-crystallin-mediated bcl-2 over-expression and on cellular resistance to apoptotic stimuli in Jurkat cells. We demonstrated that ζ-crystallin elevated bcl-2 mRNA stability through a mechanisms involving acidosis, which increased its cellular levels. In the effort to unravel the mechanisms involved in the acidosis mediated ζ-crystallin up-regulation, we revealed that acidosis activated the p38 MAPK pathway which in turn could contribute to increase ζ-crystallin expression.