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- Title
The IGF-Independent Role of IRS-2 in the Secretion of MMP-9 Enhances the Growth of Prostate Carcinoma Cell Line PC3.
- Authors
Furuta, Haruka; Sheng, Yina; Takahashi, Ayaka; Nagano, Raku; Kataoka, Naoyuki; Perks, Claire Marie; Barker, Rachel; Hakuno, Fumihiko; Takahashi, Shin-Ichiro
- Abstract
Insulin receptor substrate-2 (IRS-2), a substrate of the insulin-like growth factor (IGF)-I receptor, is highly expressed in the prostate cancer cell line, PC3. We recently demonstrated that extracellular signal-regulated kinase (Erk1/2), a kinase downstream of IGF signaling, is activated in PC3 cells under serum starvation, and this activation can be inhibited by IRS-2 knockdown. Here, we observed that adding an IGF-I-neutralizing antibody to the culture medium inhibited the activation of Erk1/2. Suppression of Erk1/2 in IRS-2 knockdown cells was restored by the addition of a PC3 serum-free conditioned medium. In contrast, the IRS-2-silenced PC3 conditioned medium could not restore Erk1/2 activation, suggesting that IRS-2 promotes the secretion of proteins that activate the IGF signaling pathway. Furthermore, gelatin zymography analysis of the conditioned medium showed that matrix metalloproteinase-9 (MMP-9) was secreted extracellularly in an IRS-2 dependent manner when PC3 was cultured under serum starvation conditions. Moreover, MMP-9 knockdown suppressed Erk1/2 activation, DNA synthesis, and migratory activity. The IRS-2 levels were positively correlated with Gleason grade in human prostate cancer tissues. These data suggest that highly expressed IRS-2 activates IGF signaling by enabling the secretion of MMP-9, which is associated with hyperproliferation and malignancy of prostate cancer cell line, PC3.
- Subjects
ANDROGEN receptors; MATRIX metalloproteinases; SOMATOMEDIN; CELL lines; SECRETION; DNA synthesis; GELATIN; INSULIN receptors
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 20, p15065
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms242015065