Illumina-microarray analysis of mycophenolic acid-induced cell death in an insulin-producing cell line and primary rat islet cells: New insights into apoptotic pathways involved

Mycophenolic acid (MPA), widely used to prevent organ transplant rejection, may induce toxicity and impair function in β-cells. Mechanisms of MPA-induced cell death have not been fully explored. In this study, we examined gene expression patterns in INS-1E cells and isolated primary rat islets following MPA treatment using the Illumina-cDNA microarray. The MPA treatment decreases RhoGDI-α gene expression, which points to apoptosis by JNK activation through a MAPKs-dependent pathway. A strong association between RhoGDI-α and Rac1 activation during MPA-induced apoptosis is also consistent with apoptosis through JNK. Suppression of RhoGDI-α using siRNA and gene over-expression both affected the cell death rate, consistent with Rac1 activation and downstream activation of MAPKs signaling. We confirmed that Rac1 protein mediates the interaction between RhoGDI-α and JNK signaling. We conclude that MPA-induced cell death in primary β-cells and an insulin-secreting cell line proceeds through RhoGDI-α down-regulation linked to Rac1 activation, with subsequent activation of JNK. The RhoGDI-α/Rac1/JNK pathway may present a key to intervention in MPA-induced islet apoptosis.