PKD1 is downregulated in non-small cell lung cancer and mediates the feedback inhibition of mTORC1-S6K1 axis in response to phorbol ester

Protein kinase D1 (PKD1) is increasingly implicated in multiple biological and molecular events that regulate the proliferation or invasiveness in several cancers. However, little is known about the expression and functions of PKD1 in non-small cell lung cancer (NSCLC). In the present study, 34 pairs of human NSCLC and matched normal bronchiolar epitheliums were enrolled and evaluated for PKD1 expression by quantitative real-time PCR. We showed that PKD1 was downregulated in 26 of 34 cancer tissues in comparison with matched normal epitheliums. Moreover, patients with venous invasion or lymph node metastasis showed significant lower expression of PKD1. Exposure of NSCLC A549 and H520 cells to the PKD family inhibitor kb NB 142-70(Kb), at concentrations that inhibited PKD1 activation, strikingly potentiated S6K1 phosphorylation at Thr389 and S6 phosphorylation at Ser235/236 in response to phorbol ester (PMA). Knockdown of PKD1 with siRNAs strikingly enhanced S6K1 phosphorylation whereas constitutively active PKD1 resulted in the S6K1 activity inhibition. Furthermore, the PI3K inhibitors LY294002, BKM120 and MEK inhibitors U0126, PD0325901 blocked the enhanced S6K1 activity induced by Kb. Collectively, our results identify decreased expression of the PKD1 as a marker for NSCLC and the loss of PKD1 expression increases the malignant potential of NSCLC cells. This may be due to the function of PKD1 as a negative regulator of mTORC1-S6K1. Our results suggest that re-expression or activation of PKD1 might serve as a potential therapeutic target for NSCLC treatment.