WISP-2/CCN5 is involved as a novel signaling intermediate in phorbol ester-protein kinase Calpha-mediated breast tumor cell proliferation.
PMA and active phorbol esters stimulate the proliferation of various tumor cells, including ER-positive human breast tumor cell lines. However, the specific signaling pathways involved in the PMA-induced mitogenic effect on breast tumor cells have not been fully elucidated. In the present study, we explored the mechanisms associated with the mitogenic influence of PMA on breast tumor cells. Following an acute exposure (i.e., within 2 to 6 h) to PMA (50 nM), a mitogenic effect was observed on WISP-2/CCN5-positive breast tumor cell lines, including MCF-7, ZR-75-1 and SKBR-3 cells, and induction of WISP-2/CCN5 mRNA expression paralleled the observed mitogenic proliferation. This effect was undetected in WISP-2/CCN5 negative MDA-MB-231 breast tumor cells or human mammary epithelial cells with or without ER-alpha transfection. The mitogenic effect of PMA was perturbed by short hairpin RNA (shRNA)-mediated inhibition of WISP-2/CCN5 signaling in MCF-7 cells. Moreover, the upregulation of WISP-2/CCN5 by PMA is not ER dependent but is instead mediated through a complex PKCalpha-MAPK/ERK and SAPK/JNK signaling pathway, which leads to growth stimulation of MCF-7 breast tumor cells. These series of experiments provide the first evidence that WISP-2/CCN5 is a novel signaling molecule that critically participates in the mitogenic action of PMA on noninvasive, WISP-2/CCN5-positive breast tumor cells through PKCalpha-dependent, multiple molecular signal transduction pathways.
Sengupta
Krishanu
K
Cancer Research Unit, V.A. Medical Center, Kansas City, Missouri, USA.
Banerjee
Snigdha
S
Dhar
Kakali
K
Saxena
Neela K
NK
Mehta
Smita
S
Campbell
Donald R
DR
Banerjee
Sushanta K
SK
D001940:Breast / Q000166:cytology; D001943:Breast Neoplasms / Q000378:metabolism*; D055511:CCN Intercellular Signaling Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004847:Epithelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D010703:Phorbol Esters / Q000494:pharmacology*; D051571:Protein Kinase C-alpha / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation
D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D010703:Phorbol Esters; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D014157:Transcription Factors; D051571:Protein Kinase C-alpha