Phospholipase C delta-4 overexpression upregulates ErbB1/2 expression, Erk signaling pathway, and proliferation in MCF-7 cells.
BACKGROUND
The expression of the rodent phosphoinositide-specific phospholipase C delta-4 (PLCdelta4) has been found to be elevated upon mitogenic stimulation and expression analysis have linked the upregulation of PLCdelta4 expression with rapid proliferation in certain rat transformed cell lines. The human homologue of PLCdelta4 has not been extensively characterized. Accordingly, we investigate the effects of overexpression of human PLCdelta4 on cell signaling and proliferation in this study.


RESULTS
The cDNA for human PLCdelta4 has been isolated and expressed ectopically in breast cancer MCF-7 cells. Overexpression of PLCdelta4 selectively activates protein kinase C-phi and upregulates the expression of epidermal growth factor receptors EGFR/erbB1 and HER2/erbB2, leading to constitutive activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway in MCF-7 cells. MCF-7 cells stably expressing PLCdelta4 demonstrates several phenotypes of transformation, such as rapid proliferation in low serum, formation of colonies in soft agar, and capacity to form densely packed spheroids in low-attachment plates. The growth signaling responses induced by PLCdelta4 are not reversible by siRNA.


CONCLUSIONS
Overexpression or dysregulated expression of PLCdelta4 may initiate oncogenesis in certain tissues through upregulation of ErbB expression and activation of ERK pathway. Since the growth responses induced by PLCdelta4 are not reversible, PLCdelta4 itself is not a suitable drug target, but enzymes in pathways activated by PLCdelta4 are potential therapeutic targets for oncogenic intervention.
Leung
David W
DW
Cell Therapeutics, Inc, 201 Elliott Ave, W, Seattle, WA 98119, USA. dwleung1@msn.com
Tompkins
Chris
C
Brewer
Jim
J
Ball
Alexey
A
Coon
Mike
M
Morris
Valerie
V
Waggoner
David
D
Singer
Jack W
JW
D000362:Agar / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D049109:Cell Proliferation; D016895:Culture Media, Serum-Free / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D018773:Genes, erbB-1; D018734:Genes, erbB-2; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000235:genetics*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics; D054803:Phospholipase C delta; D011493:Protein Kinase C / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018874:Spheroids, Cellular / Q000378:metabolism; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics*
D016895:Culture Media, Serum-Free; D007527:Isoenzymes; D034741:RNA, Small Interfering; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D000362:Agar; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010738:Type C Phospholipases; C518030:PLCD4 protein, human; D054803:Phospholipase C delta; C518032:Plcd4 protein, rat