A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle.
Protein kinase Calpha (PKCalpha) has been implicated in cancer, but the mechanism is largely unknown. Here, we show that PKCalpha promotes head and neck squamous cell carcinoma (SCCHN) by a feed-forward network leading to cell cycle deregulation. PKCalpha inhibitors decrease proliferation in SCCHN cell lines and xenografted tumors. PKCalpha inhibition or depletion in tumor cells decreases DNA synthesis by suppressing extracellular signal-regulated kinase phosphorylation and cyclin E synthesis. Additionally, PKCalpha down-regulates miR-15a, a microRNA that directly inhibits protein synthesis of cyclin E, as well as other cell cycle regulators. Furthermore, both PKCalpha and cyclin E protein expression are increased in primary tumors, and PKCalpha inversely correlates with miR-15a expression in primary tumors. Finally, PKCalpha is associated with poor prognosis in SCCHN. These results identify PKCalpha as a key regulator of SCCHN tumor cell growth by a mechanism involving activation of mitogen-activated protein kinase, an initiator of the cell cycle, and suppression of miR-15a, an 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 be a general one that enables induction of DNA synthesis by a variety of growth or oncogenic stimuli.
Cohen
Ezra E W
EE
Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Zhu
Hongyan
H
Lingen
Mark W
MW
Martin
Leslie E
LE
Kuo
Wen-Liang
WL
Choi
Eugene A
EA
Kocherginsky
Masha
M
Parker
Joel S
JS
Chung
Christine H
CH
Rosner
Marsha Rich
MR
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000502:physiology; D019927:Cyclin E / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009061:Mouth Mucosa / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D018797:Cell Cycle Proteins; D019927:Cyclin E; D004273:DNA, Neoplasm; C505361:MIRN15 microRNA, human; D035683:MicroRNAs; D051571:Protein Kinase C-alpha