Insulin-like growth factor-1 (IGF-1) induces WISP-2/CCN5 via multiple molecular cross-talks and is essential for mitogenic switch by IGF-1 axis in estrogen receptor-positive breast tumor cells.
Previously, we have shown that the expression of Wnt-1-induced signaling protein-2 (WISP-2), also known as CCN5, can be regulated by multiple stimulants in estrogen receptor (ER)-positive breast tumor cells to exert their mitogenic action in these cells. Here, we show that insulin-like growth factor-1 (IGF-1), a strong mitogen, enhanced the expression of the WISP-2/CCN5 gene parallel with the induction of proliferation of ER-positive breast tumor cells. An additive effect was also seen in combination with estrogen. Perturbation of IGF-1-induced WISP-2/CCN5 expression by WISP-2-specific RNA interference impaired the mitogenic action of IGF-1 on ER-positive breast tumor cells. Furthermore, the studies have shown that the multiple molecular cross-talks and side-talks among IGF-1R, ER-alpha, and phosphatidylinositol 3-kinase (PI3K)/Akt signaling molecules are required to induce WISP-2/CCN5 mRNA by IGF-1 in ER-positive, noninvasive breast tumor cells. Because a pure anti-ER ICI 182,780 is not only able to suppress the up-regulation of WISP-2/CCN5 mRNA expression by IGF-1, it also suppresses the PI3K/Akt activity induced by IGF-1 in MCF-7 cells; we anticipate that the membrane ER receptor may participate in this event. Collectively, these studies propose for the first time that WISP-2/CCN5 is an integral signaling molecule in mitogenic action of IGF-1 axis in ER-positive human breast tumor cells.
Dhar
Kakali
K
Cancer Research Unit, VA Medical Center, Kansas City, MO 64128, USA.
Banerjee
Snigdha
S
Dhar
Gopal
G
Sengupta
Krishanu
K
Banerjee
Sushanta K
SK
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055511:CCN Intercellular Signaling Proteins; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004357:Drug Synergism; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D012097:Repressor Proteins; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D055511:CCN Intercellular Signaling Proteins; C413323:CCN5 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D012097:Repressor Proteins; D014157:Transcription Factors; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1