PCais most common malignancy in men with poor survival rate as diseasesprogressed. We found a positive correlation of EIF4G1 expression with thedisease phenotype in TMA samples as well as with PCa cell line. A similarobservation was made with prostate tissue sections from TRAMP. Overall, wefound the expression of EIF4G1 can distinguish between the indolent andaggressive phenotype of disease and can be served as a tumor marker for betterdisease diagnosis and prognosis. Deregulatedcell cycle regulatory genes are known to associate with PCa initiation andprogression 29. In the present study, we found that knocking down of EIF4G1results delay in G0/G1 cell cycle phase that may cause apoptosis and celldeath. Thus inhibiting EIF4G1 can be used as a targeted therapy for PCa.
MostPCa death is associated with metastasis to the other organs and leads to CRPCphenotype and treatment resistance. Epithelial-to-mesenchymal transition (EMT)transition is required for cancer cells to metastasize to the distant organwhere these cells have to lose their cell properties and gain a motile andinvasive phenotype 30 and make a tumor clone (Clonogenic activity) toharboring sites. EMT is also associated with treatment resistance. Finding fromthe present study showed that EIF4G1 is required for cell migration andclonogenic activity in PCa cells. Overcoming EMT-associated drug resistance isa major goal in the clinical setting and our results showed that EIF4G1 can beused as excellent and potential therapeutic targets for treatment oftherapy-resistant PCa patients.Mostof the early stage or localized PCa can be managed and cured by local therapyor surgery. For advanced PCa first line of treatment is Androgen depletiontherapy (ADT).
As ADT fails castration-resistant or -recurrent prostate cancer(CRPC) develops in time of course due to aberrant re-activation of theandrogen/androgen receptor (AR) signaling axis 31. However next-generation ARinhibitors such enzalutamide (ENZ) increases the overall survival of CRPCpatients 32,33; still, there is therapy resistance in some patients 34.Considering our findings for EIF4G1 in PCa, the available inhibitor ofEIF4E-EIF4G1 complex i.e. 4EGI-1 can be used in combination with ENZ that maysensitize the CRPC cells to current therapy. Ongoing studies in our laboratoryare going on to address this possible combination therapy and preliminaryfindings are supportive (data not shown).
Conclusion:Thebeneficial effect of targeting translation lies within its strength to affectthe expression of multiple oncogenic pathways that are associated with diseaseand progression. The potential of targeting translational machinery will helpthe patients with failure in targeted therapies or can be combined with currenttherapy in PCa treatment for improving the disease outcome. Overall, our dataindicate that EIF4G1 may function as an oncoprotein and is a novel target forintervention in PCa and CRPC.