Cancer research
-
Matrix metalloproteinase-2 (MMP-2) expression is often up-regulated in advanced cancers and known to play an important role in tumor angiogenesis. We previously showed that adenoviral-mediated delivery of siRNA for MMP-2 (Ad-MMP-2-Si) inhibited lung cancer growth, angiogenesis, and metastasis. In this study, we investigated the signaling mechanisms involved in Ad-MMP-2-Si-mediated inhibition of angiogenesis. ⋯ Vasculature destruction was confirmed with colocalization studies with TUNEL and an endothelial marker, CD31, in tumor sections of Ad-MMP-2-Si-treated mice. Our data collectively suggest that MMP-2 inhibition induces endothelial apoptosis in vivo and inhibits endothelial tube formation. These experiments provide the first evidence that inhibition of p-AKT and induction of p-ERK1/2 are crucial events in the induction of TIMP-3-mediated endothelial apoptosis in MMP-2 inhibited lung tumors.
-
Androgen receptor (AR)- and glucocorticoid receptor (GR)- mediated signaling play opposite roles in prostate tumorigenesis: AR promotes prostate carcinoma (PC) development, whereas GR acts as a tumor suppressor. Compound A (CpdA) is a stable analogue of an aziridine precursor from the African shrub Salsola tuberculatiformis Botschantzev. It was shown recently that, in model cells, CpdA inhibits AR function and strongly enhances anti-inflammatory function of GR. ⋯ The cytostatic effect of CpdA is receptor dependent: down-regulation of GR or AR expression drastically attenuates CpdA-induced PC cell growth inhibition. Finally, virtual docking analysis indicates that CpdA shares binding cavities in AR and GR ligand-binding domains with corresponding hormones and forms hydrogen bonds (H-bond) with the same amino acids that are involved in H-bond formation during steroid binding. Overall, our data suggest that CpdA is a unique dual-target steroid receptor modulator that has a high potential for PC therapy.
-
The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) has shown potential as a chemopreventive and therapeutic agent. The ability of 4HPR to enhance production of reactive oxygen species (ROS) leading to apoptosis has been suggested as a possible mechanism underlying these effects. We explored the possibility that ROS induction by 4HPR involves the small GTPase Ras-related C3 botulinum toxin substrate (Rac), a regulatory subunit of the NADPH oxidase complex. ⋯ In addition, the metastatic DM14 cells exhibited higher Rac activation following 4HPR treatment compared with the primary Tu167-C2 cells. Furthermore, the metastatic cancer cells tested exhibited higher ROS generation and growth inhibition due to 4HPR exposure compared with their primary cancer cell counterparts. These findings show a preferential susceptibility of metastatic cells to the proapoptotic retinoid 4HPR through Rac activation and support the use of ROS-inducing agents such as 4HPR against metastatic cancer cells.