TRAF4 knockdown triggers synergistic lethality with simultaneous PARP1 inhibition in endometrial cancer

: Endometrial cancer (EC) is one of the most common cancers among females worldwide. Advanced stage patients of EC have poor prognosis. Inevitable side effects and treatment tolerance of chemotherapy for EC remain to be addressed. Our results in this study showed that EC cells with higher tumor necrosis factor receptor-associated factor 4 (TRAF4) expression have lower sensitivity to poly ADP-ribose polymerase 1 (PARP1) inhibitors. Upon TRAF4 knockdown, the colony numbers of EC cells were markedly down-regulated, and the markers of DNA double-strand breakage were significantly up-regulated after the treatment of olaparib, a PARP1 inhibitor. TRAF4 knockdown reduced the phosphorylation of protein kinase B (Akt), promoted DNA double-strand breakage, and decreased levels of DNA repair related proteins, including phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). In addition, TRAF4's effect on the sensitivity of EC cells to olaparib was further found to be mainly mediated by Akt phosphorylation. Moreover, in vivo results showed that TRAF4 knockdown enhanced the sensitivity of EC to PARP1 inhibitors using a mouse xenograft model. Collectively, our data suggest that combined application of TRAF4 knockdown and PARP1 inhibition can be used as a promising strategy for synthetic lethality in EC treatment.