CID755673 enhances mitogenic signaling by phorbol esters, bombesin and EGF through a protein kinase D-independent pathway

Recently, CID755673 has been identified as a highly selective inhibitor of protein kinase D (PKD). However, during experiments with CID755673, we observed unexpected stimulatory effects on [(3)H]thymidine incorporation and cell cycle progression in Swiss 3T3 cells stimulated by bombesin (a Gq-coupled receptor agonist), phorbol 12,13-dibutyrate (PDBu, a biologically active phorbol ester known to promote tumors), and epidermal growth factor (EGF). These stimulatory effects persisted despite the inhibitory action of CID755673 on PKD activity, as evidenced by continued enhancement of DNA synthesis in cells where PKD1 was severely down-regulated following siRNA-mediated knockdown.

Our study highlights a critical issue: CID755673 should not be regarded as a specific PKD inhibitor. Its use in experiments aimed at understanding the role of PKD family members in cellular regulation, especially in cell cycle progression from G(1)/G(o) to S phase, should be approached with caution.