ABSTRACT
Programmed cell death 4 (Pdcd4) is frequently suppressed in tumors of various origins and its suppression correlates with tumor progression. Pdcd4 inhibits cap-dependent translation from mRNAs with highly structured 5'-regions through interaction with the eukaryotic translation initiation factor 4A (eIF4A) helicase and a target transcript. Decrease in Pdcd4 protein is believed to provide a relief of otherwise suppressed eIF4A-dependent translation of proteins facilitating tumor progression. However, it remains unknown if lowered Pdcd4 levels in cells suffices to cause a relief in translation inhibition through appearance of the Pdcd4-free translation-competent eIF4A protein, or more complex and selective mechanisms are involved. Here we showed that eIF4A1, the eIF4A isoform involved in translation, significantly over-represents Pdcd4 both in cancerous and normal cells. This observation excludes the possibility that cytoplasmic Pdcd4 can efficiently exert its translation suppression function owing to excess of eIF4A, with Pdcd4-free eIF4A being in excess over Pdcd4-bound translation-incompetent eIF4A, thus leaving translation from Pdcd4 mRNA targets unaffected. This contradiction is resumed in the proposed model, which supposes initial complexing between Pdcd4 and its target mRNAs in the nucleus, with subsequent transport of translation-incompetent, Pdcd4-bound target mRNAs into the cytoplasm. Noteworthy, loss of nuclear Pdcd4 in cancer cells was reported to correlate with tumor progression, which supports the proposed model of Pdcd4 functioning.
Subject(s)
Apoptosis Regulatory Proteins/genetics , Eukaryotic Initiation Factor-4A/genetics , Gene Expression Regulation, Neoplastic , Neoplasms/genetics , RNA, Messenger/genetics , RNA-Binding Proteins/genetics , Apoptosis Regulatory Proteins/metabolism , Biological Transport , Cell Death/genetics , Cell Nucleus/metabolism , Cytoplasm/metabolism , Eukaryotic Initiation Factor-4A/metabolism , Humans , Models, Genetic , Neoplasms/metabolism , Neoplasms/pathology , Protein Binding , Protein Biosynthesis , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , Signal TransductionABSTRACT
BACKGROUND: Programmed cell death 4 (Pdcd4) is a tumor suppressor frequently lost in tumors of various origins thus contributing to tumor progression. Expression of Pdcd4 in melanoma, however, has not been extensively studied to date. MATERIALS AND METHODS: Pdcd4 protein levels were assessed in 23 human melanoma cell lines and in normal melanocytes by western blot analysis. Also, effects of LY294002, rapamycin and PD098059 on Pdcd4 protein levels were analyzed. RESULTS: Pdcd4 is suppressed in ~25% of human cell lines established from advanced melanoma lesions. Pdcd4 protein levels in melanoma cells were up-regulated by treatment with inhibitors of Akt signaling, one of the key pathways leading to Pdcd4 suppression, and to a lesser extent by inhibiting MEK/ERK pathway. CONCLUSION: Pdcd4 loss is not a common event in melanoma progression yet suppression of Pdcd4 defines a subset of melanoma cells and can be used for molecular typing of melanoma. Our results help determine the significance of Pdcd4 loss in melanoma as well as its up-regulation by Akt pathway inhibitors, which are promising tools in melanoma treatment.
