Regulation of β1C and β1A integrin expression in prostate carcinoma cells.

Abstract

β1C and β1A integrins are two splice variants of the human β1 integrin subfamily that act as an inhibitor and a stimulator of cell proliferation, respectively. In neoplastic prostate epithelium, both these variants are down-regulated at the mRNA level, but only β1C protein levels are reduced. We used an experimental model consisting of PNT1A, a normal immortalized prostate cell line, and LNCaP and PC-3, two prostate carcinoma cell lines, to investigate both the transcription/post-transcription and translation/post-translation processes of β1C and β1A. Transcriptional regulation played the key role for the reduction in β1C and β1A mRNA expression in cancer cells, as β1C and β1A mRNA half-lives were comparable in normal and cancer cells. β1C translation rate decreased in cancer cells in agreement with the decrease in mRNA levels, whereas β1A translation rate increased more than 2-fold, despite the reduction in mRNA levels. Both β1C and β1A proteins were degraded more rapidly in cancer than in normal cells, and pulse-chase experiments showed that intermediates and/or rates of β1C and β1A protein maturation differ in cancer versus normal cells. Inhibition of either calpain- or lysosomal-mediated proteolysis increased both β1C and β1A protein levels, the former in normal but not in cancer cells and the latter in both cell types, albeit at a higher extent in cancer than in normal cells. Interestingly, inhibition of the ubiquitin proteolytic pathway increased expression of ubiquitinated β1C protein without affecting β1A protein levels in cancer cells. These results show that transcriptional, translational, and post-translational processes, the last involving the ubiquitin proteolytic pathway, contribute to the selective loss of β1C integrin, a very efficient inhibitor of cell proliferation, in prostate malignant transformation.