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