A Feed-Forward Loop Involving Protein Kinase Cα and MicroRNAs Regulates Tumor Cell Cycle

Protein kinase C alpha (PKC alpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKC alpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKC alpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKC alpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKC alpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKC alpha and cyclin E Protein expression are increased in primary tumors, and PKC alpha inversely correlates with miR-15a expression in primary tumors. Finally, PKC alpha is associated with poor prognosis in SCCHN. These results identify PKC alpha as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, art initiator of the cell cycle, and suppression of miR-15a, tin inhibitor of DNA synthesis. Although the specific components may be different, this type of feed-forward loop network, consisting of a stimulus that activates a positive signal and removes a negative brake, is likely to he a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli. [Cancer Res 2009;69(1):65-74]