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Discussion:

PCa is most common malignancy in men with poor survival rate as diseases progressed. EIF4G1, which is an RNA-binding protein (RBP), acts as a scaffold protein that together with eIF4E and eIF4A helps to recognize the 5′ end of the mRNA to initiate the translation and help in mRNA recruitment to the ribosome assembly 29. Further EIF4G1 can put together the 5′ and 3′ ends of the mRNA to form a ‘closed-loop structure by interacting with the other RBPs that play a role in termination and recycling of translation machinery with subsequent translation initiation on the same mRNA 30.

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We found a positive correlation of EIF4G1 expression with the disease phenotype in TMA samples as well as with PCa cell line. A similar observation was made with prostate tissue sections from TRAMP. Overall, we found the expression of EIF4G1 can distinguish between the indolent and aggressive phenotype of disease and can be served as a tumor marker for better disease diagnosis and prognosis.

Deregulated cell cycle regulatory genes are known to associate with PCa initiation and progression 31. In the present study, we found that knocking down of EIF4G1 results delay in G0/G1 cell cycle phase that may cause apoptosis and cell death. Thus inhibiting EIF4G1 can be used as a targeted therapy for PCa.

Most PCa death is associated with metastasis to the other organs and leads to CRPC phenotype and treatment resistance. Epithelial-to-mesenchymal transition (EMT) transition is required for cancer cells to metastasize to the distant organ where these cells have to lose their cell properties and gain a motile and invasive phenotype 32 and make a tumor clone (Clonogenic activity) to harboring sites. EMT is also associated with treatment resistance. Finding from the present study showed that EIF4G1 is required for cell migration and clonogenic activity in PCa cells. Overcoming EMT-associated drug resistance is a major goal in the clinical setting and our results showed that EIF4G1 can be used as excellent and potential therapeutic targets for treatment of therapy-resistant PCa patients.

Most of the early stage or localized PCa can be managed and cured by local therapy or surgery. For advanced PCa first line of treatment is Androgen depletion therapy (ADT). As ADT fails castration-resistant or -recurrent prostate cancer (CRPC) develops in time of course due to aberrant re-activation of the androgen/androgen receptor (AR) signaling axis 33. However next-generation AR inhibitors such enzalutamide (ENZ) increases the overall survival of CRPC patients 34,35; still, there is therapy resistance in some patients 36. Considering our findings for EIF4G1 in PCa, the available inhibitor of EIF4E-EIF4GI complex i.e. 4EGI-1 can be used in combination with ENZ that may sensitize the CRPC cells to current therapy. Ongoing studies in our laboratory are going on to address this possible combination therapy and preliminary findings are supportive (data not shown).

Conclusion:

The beneficial effect of targeting translation lies within its strength to affect the expression of multiple oncogenic pathways that are associated with disease and progression. The potential of targeting translational machinery will help the patients with failure in targeted therapies or can be combined with current therapy in PCa treatment for improving the disease outcome. Overall, our data indicate that EIF4G1 may function as an oncoprotein and is a novel target for intervention in PCa and CRPC.

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