Leupaxin acts as a mediator in prostate carcinoma progression through deregulation of p120catenin expression

Abstract

Recently, we could show that the focal adhesion protein leupaxin (LPXN) is expressed in human prostate carcinomas (PCa) and induces invasiveness of androgenindependent PCa cells. In this study we show that LPXN enhanced the progression of existing PCa in vivo by breeding transgenic mice with prostate-specific LPXN expression and TRAMP mice (transgenic adenocarcinoma of mouse prostate). Double transgenic LPXN/ TRAMP mice showed a significant increase in poorly differentiated PCa and distant metastases as compared with control TRAMP mice. Additional studies on primary PCa cells generated from both transgenic backgrounds confirmed the connection regarding LPXN overexpression and increased motility and invasiveness of PCa cells. One mediator of LPXN-induced invasion was found to be the cell-cell adhesion protein p120catenin (p120CTN). Both in vitro and in vivo experiments revealed that p120CTN expression negatively correlates with LPXN expression, followed by a redistribution of b-catenin. Downregulation of LPXN using small interfering RNAs (siRNAs) resulted in a membranous localization of b-catenin, whereas strong nuclear accumulation of b-catenin was observed in p120CTN knockdown cells leading to enhanced transcription of the b-catenin target gene matrix metalloprotease-7. In conclusion, the present results indicate that LPXN enhances the progression of PCa through downregulation of p120CTN expression and that LPXN could function as a marker for aggressive PCa in the future.

E3 Ubiquitin Ligase RNF126 Promotes Cancer Cell Proliferation by Targeting the Tumor Suppressor p21 for Ubiquitin-Mediated Degradation

“…Limited evidence suggests that several of them are oncogenic E3 ligases. For example, SYVN1 has been shown to target p53 and gp78 for degradation (31,32), LPXN may promote prostate cancer metastasis by serving as a co-activator of androgen receptors (33,34), and TRIM8 may promote STAT3 and NF-kB activation (35,36). These candidate E3 ligases warrant further investigation.…”

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…The paxillin homologue leupaxin, a 45 kDa protein with ≈ 37% homology to paxillin, was originally characterized as a multi-functional adaptor protein expressed only in hematopoietic cells [87,[89][90][91]. However, leupaxin, like both Hic-5 and paxillin, has been recently shown to be expressed in a subset of human prostate cancers, accumulating in the nucleus to potentiate androgen receptor (AR) transactivation in a ligand-dependent manner [87,92,93].…”

“…Irrespective of their cell-type-specific expression profiles, all members of the paxillin superfamily are classified as group III LIM domain proteins which, by definition stipulates that this family of proteins is predominantly found in the cytoplasm interacting with cytoskeletal proteins [87,[90][91][92]95]. However, they have also been shown to shuttle into the nucleus and act as transcriptional co-activators of androgen and glucocorticoid receptor signaling cascades [66].…”

“…Conversely, the C-terminal LIM domain, specifically LIM3 in cooperation with LIM2 has been shown to mediate the discrete subcellular targeting of the protein to both the actin cytoskeleton and focal adhesions; the LIM domain is also believed to be required for localization of paxillin to the nucleus [66,90].…”

Matricellular protein SPARCL1 regulates tumor microenvironment–dependent endothelial cell heterogeneity in colorectal carcinoma

“…The top 50 upregulated and downregulated genes are depicted in a heatmap ( Figure 3B; blue: antitumorigenic genes are indicated by arrows, and antiangiogenic genes are indicated by arrowheads; pink: tumorigenic genes are indicated by arrows, and angiogenic genes are indicated by arrowheads) and are presented in full detail in Supplemental hi TECs characterized by a Th1-TME. Among the most strongly downregulated genes, tumorigenic genes such as LAMC2 (31), leupaxin (32), or ADAM12 (33), and angiogenic genes, such as SERPIND1 (34), HEY2 (35), or EDIL3 (36) were detected. Accordingly, gene expression in the TECs within the GBP-1 hi group reflected the intertumoral activity (angiostatic and antitumorigenic) associated with the Th1-TME in CRC.…”