Synergistic Antiproliferative Effects of All-Trans Retinoic Acid and Paclitaxel on Autosomal Dominant Polycystic Kidney Disease Epithelial Cells

Figure 6

Proposed mechanisms underlying the antiproliferative effect of the combination of PAC and ATRA on ADPKD cells. In ADPKD, the lower intracellular Ca²⁺ level owing to PC1/PC2 dysfunction results in the activation of the mitogenic effect of cAMP-dependent B-raf, thereby triggering cell proliferation through MEK/ERK activation. The stimulation with PAC and ATRA results in the activation of the plasma membrane Ca²⁺ channels, leading to an increase in the intracellular Ca²⁺ levels in ADPKD cells. Enhanced Ca²⁺ levels activate MKP-1, which subsequently inhibits ERK phosphorylation. As a result, these upstream events induce cell cycle arrest and apoptosis, consequently suppressing ADPKD cell proliferation. The dotted line indicates a mechanism proposed by Yamaguchi et al. [24] that increased intracellular Ca²⁺ levels can suppress cAMP-dependent B-Raf activation.