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Integrin ?2?1 decelerates proliferation, but promotes survival and invasion of prostate cancer cells.

ABSTRACT: High expression level of integrin ?2?1 is a hallmark of prostate cancer stem cell like cells. The role of this collagen receptor is controversial since it is down regulated in poorly differentiated carcinomas, but concomitantly proposed to promote metastasis. Here, we show that docetaxel resistant DU145 prostate cancer cells express high levels of ?2?1 and that ?2?1^High subpopulation of DU145 cells proliferates slower than the cells representing ?2?1^Low subpopulation. To further study this initial observation we used Crispr/Cas9 technology to create an ?2?1 negative DU145 cell line. Furthermore, we performed rescue experiment by transfecting ?2 knockout cells with vector carrying ?2 cDNA or with an empty vector for appropriate control. When these two cell lines were compared, ?2?1 positive cells proliferated slower, were more resistant to docetaxel and also migrated more effectively on collagen and invaded faster through matrigel or collagen. Integrin ?2?1 was demonstrated to be a positive regulator of p38 MAPK phosphorylation and a selective p38 inhibitor (SB203580) promoted proliferation and inhibited invasion. Effects of ?2?1 integrin on the global gene expression pattern of DU145 cells in spheroid cultures were studied by RNA sequencing. Integrin ?2?1 was shown to regulate several cancer progression related genes, most notably matrix metalloproteinase-1 (MMP-1), a recognized invasion promoting protein. To conclude, the fact that ?2?1 decelerates cell proliferation may explain the dominance of ?2?1 negative/low cells in primary sites of poorly differentiated carcinomas, while the critical role of ?2?1 integrin in invasion stresses the importance of this adhesion receptor in cancer dissemination.

SUBMITTER: Ojalill M

PROVIDER: S-EPMC6126696 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Integrin α2β1 decelerates proliferation, but promotes survival and invasion of prostate cancer cells.

Ojalill Marjaana M Parikainen Marjaana M Rappu Pekka P Aalto Elina E Jokinen Johanna J Virtanen Noora N Siljamäki Elina E Heino Jyrki J

Oncotarget 20180821 65

High expression level of integrin α2β1 is a hallmark of prostate cancer stem cell like cells. The role of this collagen receptor is controversial since it is down regulated in poorly differentiated carcinomas, but concomitantly proposed to promote metastasis. Here, we show that docetaxel resistant DU145 prostate cancer cells express high levels of α2β1 and that α2β1<sup>High</sup> subpopulation of DU145 cells proliferates slower than the cells representing α2β1<sup>Low</sup> subpopulation. To fu ...[more]

PMID: 30197754

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Project description:BackgroundIntegrin α2β1 inhibitor BTT-3033 (1-(4-fluorophenyl)-N-methyl-N-[4[[(phenylamino)carbonyl]amino]phenyl]-1H-pyrazole-4-sulfonamide) was recently reported to inhibit neurogenic and thromboxane A2-induced human prostate smooth muscle contraction, and thus represents a target with a different inhibition spectrum than that of α1-blockers in benign prostate hyperplasia (BPH) treatments. Clarifying the underlying mechanisms of the inhibition effects will provide insights into the role of integrin α2β1 in prostate contraction and enable new intracellular targets for smooth muscle contraction to be explored.MethodsProteomeHD was used to predict and enrich the top co-regulated proteins of integrin α2 (ITGA2). A phosphoproteomic analysis was conducted on human prostate stromal cells (WPMY-1) treated with 1 or 10 µM of BTT-3033 or solvent for controls. A clustering analysis was conducted to identify the intracellular targets that were inhibited in a dose-dependent manner. Gene ontology (GO) and annotation enrichments were conducted to examine any functional alterations and identify possible downstream targets. A Kinase-substrate enrichment analysis (KSEA) was conducted to identify kinases-substrate relationships.ResultsEnrichments of the actin cytoskeleton and guanosine triphosphatases (GTPases) signaling were predicted from the co-regulated proteins with ITGA2. LIM domain kinases, including LIM domain and actin-binding 1 (LIMA1), zyxin (ZYX), and thyroid receptor-interacting protein 6 (TRIP6), which are functionally associated with focal adhesions and the cytoskeleton, were present in the clusters with dose-dependent phosphorylation inhibition pattern. 15 substrates were dose-dependently inhibited according to the KSEA, including polo-like kinase 1 (PLK1), and GTPases signaling proteins, such as disheveled segment polarity protein 2 (DVL2).ConclusionsIn this study, we proposed that the mechanisms underlying the contractile and proliferative effects of integrin α2β1 are the LIM domain kinases, including the ZYX family, and substrates, including PLK1 and DVL2.

Dataset Information

Integrin ?2?1 decelerates proliferation, but promotes survival and invasion of prostate cancer cells.

Publications

Integrin α2β1 decelerates proliferation, but promotes survival and invasion of prostate cancer cells.

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