Abstract 4125: Suppression of the mevalonate pathway and oncogenic signaling may underlie the tumor-suppressing effects of KLK5 in breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Kallikrein-related peptidase 5 (KLK5) has been implicated in different types of cancer based on its aberrant expression in tumor cell lines and tissue specimens and in vitro data, however, functional association is missing. Here, we confirmed that KLK5 is very frequently down-regulated or inactivated in breast cancers of different subtypes. Reconstitution of KLK5 expression by stable transfection in KLK5-negative MDA-MB-231 cells remarkably reversed their malignant phenotype both in vitro (wound scratch and soft agar assay) and in vivo (orthotopic xenograft growth in SCID mice). We found that in KLK5 transfectants Snail1 and the mesenchymal marker vimentin were highly downregulated, pointing to a potential involvement of KLK5 in mesenchymal-to-epithelial transdifferentiation, however, re-expression of E-cadherin could not be demonstrated. Importantly, it appears that KLK5 may severely affect the overall output of the proteolytic web as it minimized the proteolytic activities of MMP9 and MMP3. Unexpectedly, transcriptomic profiling revealed that reconstitution of KLK5 expression suppresses the mevalonate pathway of cholesterol biosynthesis by highly up-regulating INSIG1 (insulin induced gene 1), a major negative regulator of HMGCR (3-hydroxy-3-methylgluratyl-CoA reductase), while KLK5 may also affect cholesterol uptake, as the LDLR (LDL receptor) and PCSK9 (proprotein convertase subtilisin-like/kexin type 9), the main regulator of LDLR, were both found significantly upregulated in KLK5 transfectants. A functional role of KLK5 in the regulation of the mevalonate pathway and protein-prenylation circuitries was demonstrated by reduced cellular cholesterol and prenylation levels, end products of this pathway. Reduced prenylation was shown by the remarkable reduction in the levels of activated RhoA, which must be subjected to isoprenylation (mainly geranyl-geranylation) for activation. To our knowledge, this is the first demonstration of a protease involved in the crosstalk between metabolic pathways and oncogenic signaling. Moreover, among the genes found up or down-regulated upon KLK5 re-expression (i.e. the “KLK5 signature”) were several genes known to be involved in atherosclerosis and other lipid-related metabolic disorders. Overall, KLK5 may represent a nodal interconnection of proteolytic and signaling pathways in cancer but may also participate in pathways associated with metabolic diseases, in support of the emerging concept of common genetic networks governing both cancer and lipid-associated disorders. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4125. doi:1538-7445.AM2012-4125