Epidermal Expression of the Translation Inhibitor Programmed Cell Death 4 Suppresses Tumorigenesis

Abstract

Programmed cell death 4 (Pdcd4) is a novel repressor of in vitro transformation. Pdcd4 directly inhibits the helicase activity of eukaryotic translation initiation factor 4A, a component of the translation initiation complex. To ascertain whether Pdcd4 suppresses tumor development in vivo, we have generated transgenic mice that overexpress Pdcd4 in the epidermis (K14-Pdcd4). K14-regulated Pdcd4 expression caused a neonatal short-hair phenotype due to early catagen entry compared with matched wild-type siblings. In response to the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) mouse skin carcinogenesis protocol, K14-Pdcd4 mice showed significant reductions in papilloma formation, carcinoma incidence, and papilloma-to-carcinoma conversion frequency compared with wild-type mice. The translational efficiency of an mRNA engineered to form a structured 5V untranslated region (UTR) was attenuated in primary keratinocytes when Pdcd4 was overexpressed. Pdcd4 inhibited by 46% TPA-induced activator protein-1 (AP-1)-dependent transcription, an event required for tumorigenesis. CDK4 and ornithine decarboxylase (ODC) are candidates for Pdcd4-regulated translation as their mRNAs contain 5Vstructured UTRs. In K14-Pdcd4 primary keratinocytes expressing activated Ha-Ras to mimic DMBA-initiated epidermis, ODC and CDK4 protein levels were decreased by 40% and 46%, respectively. Expression of a protein encoded by 5V unstructured mRNA showed no change. These results extend to an in vivo model the observations that Pdcd4 inhibits both translation initiation and AP-1 activation while decreasing benign tumor development and malignant progression. The K14-Pdcd4 mice seem to validate translation initiation as a novel target for cancer prevention. (Cancer Res 2005; 65(14): 6034-41)

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

“…Because of its ability to suppress neoplastic transformation both in vitro (Yang et al, 2003b) and in vivo (Jansen et al, 2005), PDCD4 represents a critical target of miR-21 in oncogenesis. The downregulation of PDCD4 represents a major determinant of the effect of miR-21 on invasion and metastasis in colorectal and breast cancer, in which PDCD4 expression exhibits an Figure 3).…”

Tumor suppressor Pdcd4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors

“…progression (Jansen et al, 2005), invasion and matrix metalloproteinase activation (Yang et al, 2006) and tumor growth (Stalberg et al, 2001). It is also identified as a correlate of induced apoptosis (Shibahara et al, 1995;Zhang and DuBois, 2001) and cellular senescence (Kang et al, 2002).…”

“…Pdcd4 has been described recently as a new tumor suppressor gene, its overexpression being sufficient to inhibit 12-O-Tetradecanoylphorbol 13-acetate 4b,9a, 12b,13a,20-Pentahydroxytiglia-1,6-dien-3-one 12-tetradecanoate 13-acetate (TPA)-induced neoplastic transformation (Cmarik et al, 1999;Yang et al, 2001a), as well as tumor promotion and progression to carcinomas in a transgenic mouse model (Jansen et al, 2005). It was identified in the JB6 mouse epidermal clonal genetic variant cell system as a 64 kDa protein, being preferentially expressed in tumor-promoter-resistant cells and suppressed in promotion-sensitive cells undergoing neoplastic transformation (Cmarik et al, 1999).…”

“…Pdcd4 has been suggested to be linked to the process of apoptosis in response to different inducers (Shibahara et al, 1995;Zhang and DuBois, 2001), and has been shown to be regulated by topoisomerase inhibitors (Onishi et al, 1998), COX-2 inhibitors (Zhang and DuBois, 2001), Myb (Schlichter et al, 2001) and Akt (Palamarchuk et al, 2005). Molecules regulated by Pdcd4 include p21 (Go¨ke et al, 2004), Cdk4, ornithine decarboxylase (Jansen et al, 2005), carbonic anhydrase II (LankatButtgereit et al, 2004) and JNK/c-Jun/AP-1 (Bitomsky et al, 2004;Yang et al, 2006). Pdcd4 interacts with the translation initiation factors eIF4A and eIF4G and inhibits translation (Yang et al, 2004;Zakowicz et al, 2005).…”

Programmed Cell Death 4 inhibits breast cancer cell invasion by increasing Tissue Inhibitor of Metalloproteinases-2 expression

“…[8] demonstrated that inhibition of COX-2 by the selective inhibitor NS398 increased the mRNA expression of Programmed Cell Death 4 (PDCD4) in colon cancer cells. PDCD4 suppresses the in vitro transformation of mouse keratinocytes induced by 12-Otetradecanoylphorbol-13-acetate (TPA) [9,10] and the promotion and progression of skin carcinogenesis in response to 7,12-dimethylbenz(a)anthracene/TPA in animal models [11]. PDCD4 interacts with translation initiation factors eIF4A and eIF4G and inhibits AP-1 transactivation [9,12].…”