Modulating translation initiation in prostate cancer with the tetrathiomolybdate ATN-224

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Prostate cancer is currently the most diagnosed cancer in men. While treatment is very successful when caught early, metastasis of the primary tumor is the cause of 85 percent of prostate cancer deaths. Many changes are acquired to allow the cancer cell to gain metastatic potential, most notably an epithelial-mesenchymal transition. Translation initiation factors such as eIF4E have been shown to be overexpressed in many types of progressive cancer, implicating changes in translation as a mechanistic cause for transformation of proliferative cancer cells into invasive and metastatic cells. The mechanism responsible for this involves selectively increased translation efficiency of mRNA that have complex 5’ untranslated regions, which includes mRNA for many oncogenes and growth controlling genes. We have identified a number of proteases and metastasis-related genes that have shaped our current hypothesis that changes in the regulation of translation initiation are correlated with the metastatic potential of cancer cells. In order to inhibit the translation machinery, we have used ATN-224, a second-generation tetrathiomolybdate. ATN-224 is in clinical development and has been shown to be a copper chelator, an NFkB inhibitor and an inhibitor of superoxide dismutase (SOD)-1. Using the LNCaP, C4-2, and C4-2B₄ cell lines as a genetically related model for bone-metastasizing prostate cancer, we saw a much higher level of eIF4E in the C4-2 and C4-2B₄ cell lines than in the parental LNCaP line which was blocked with ATN-224. In the LNCaP line, ATN-224 blocked IGF-stimulated phospho-Akt. In the PC-3 and MDA 2b cell lines, ATN-224 significantly reduced the amount of IGF-stimulated phosphorylated p38, RSK-1, GSK-3beta, and Akt family members in PC-3. In addition, in MDA 2b, ATN-224 significantly reduced the amount of IGF-stimulated JNK1, JNK2, JNK, Akt family members, p38, and RSK-1. Blocking phosphorylation and subsequent activation of RSK-1, RSK-2, Akt, Erk, p38, JNK family members, and GSK-3β have all been identified as potential targets for anti-cancer therapy. The mechanism underlying these changes in translational players is an ongoing effort in our lab, with an emphasis on differences in cell lines that do or do not metastasize specifically to bone. In primary tumors or distant metastatic sites, ATN-224 has great potential as a new adjuvant therapy in advanced prostate cancer. Ultimately, identifying changes in components of the translational machinery or upstream signaling in pathways that regulate translation initiation will improve our approach to therapy. Since a ‘silver bullet’ is unlikely, using treatments that act on multiple pathways in cancer progression is a patient’s best hope at successfully managing his disease.