The MDA-9/Syntenin/IGF1R/STAT3 Axis Directs Prostate Cancer Invasion

Abstract

Although prostate cancer is clinically manageable during several stages of progression, survival is severely compromised once cells invade and metastasize to distant organs. Comprehending the pathobiology of invasion is required for developing efficacious targeted therapies against metastasis. Based on bioinformatics data, we predicted an association of melanoma differentiation-associated gene-9 [syntenin, or syndecan binding protein (SDCBP)] in prostate cancer progression. Using tissue samples from various Gleason stage prostate cancer patients with adjacent normal tissue, a series of normal prostate and prostate cancer cell lines (with differing tumorigenic/metastatic properties), -manipulated variants (including loss-of-function and gain-of-function cell lines), and CRISPR/Cas9 stable MDA-9/Syntenin knockout cells, we now confirm the relevance of and dependence on MDA-9/syntenin in prostate cancer invasion. MDA-9/Syntenin physically interacted with insulin-like growth factor-1 receptor following treatment with insulin-like growth factor binding protein-2 (IGFBP2), regulating downstream signaling processes that enabled STAT3 phosphorylation. This activation enhanced expression of MMP2 and MMP9, two established enzymes that positively regulate invasion. In addition, MDA-9/syntenin-mediated upregulation of proangiogenic factors including IGFBP2, IL6, IL8, and VEGFA also facilitated migration of prostate cancer cells. Collectively, our results draw attention to MDA-9/Syntenin as a positive regulator of prostate cancer metastasis, and the potential application of targeting this molecule to inhibit invasion and metastasis in prostate cancer and potentially other cancers. This study provides new mechanistic insight into the proinvasive role of MDA-9/Syntenin in prostate cancer and has potential for therapeutic application to prevent prostate cancer metastasis. .

MDA-9/Syntenin (SDCBP) Is a Critical Regulator of Chemoresistance, Survival and Stemness in Prostate Cancer Stem Cells

“…We now demonstrate that MDA-9 may be such a crucial element, which has a central regulatory role in the survival and maintenance as well as chemoresistance of PCSCs. MDA-9 physically interacts with IGF-1R, thereby regulating STAT3 phosphorylation at Tyr-705 [46,68]. By regulating STAT3 and C-myc, MDA-9 contributes to the observed resistance to docetaxel and trichostatin A (Figures 3 and 4, Supplementary Figures S2, S3 and S5).…”

PDZ Domains as Drug Targets

“…Several NMR and X-ray crystal structures of ligands bound to syntenin reveal that interaction selectivity of the PDZ2 domain is determined by a combination of three binding pockets that bind amino acid side chains with different properties (Figure 11c,d,f). [36,248,249] The PDZ domains of syntenin have also been found to interact with membrane lipids. Structural analysis of PDZ2 bound to various peptide ligands reveals that the binding site can induce conformational changes in the α2 helix, and thus adopt an induced fit, depending on the specific interaction partner.…”

IGF signalling in germ cells and testicular germ cell tumours: roles and therapeutic approaches

“…Matrix metalloproteinases are induced by IGF1 (Yoon & Hurta, ), conferring an invasive phenotype (Das et al ., ), and MMP‐2 and MMP‐9 are frequently expressed in non‐seminomas (Gilbert et al ., ). IGF1 can also induce VEGF ligands and upregulate vascular vessel formation, thereby exhibiting pro‐angiogenic properties (Kurmasheva et al ., ; Li et al ., ).…”