Untitled

Abstract

Extensive studies have led to the identification of protein-protein interaction (PPI) cores and intersections that are critical for the acquisition and maintenance of properties of malignant transformation [1]. With technological advances in PPI modulator discovery and validation of PPI-targeting agents, for instance, several small-molecule PPI antagonists that target the interactions of MDM2/p53, XIAP/caspase-9 and BCL2/beclin1 are being studied in clinical trials for cancer patients; targeting of PPI interfaces as an anticancer strategy has come to a reality gradually. This development is likely to continue in light of the huge market and application prospects [1]. Therefore, identifying new small-molecule PPI modulators have advanced clinical perspective for cancer therapy.Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα that induces the differentiation block and the transcriptional repression, and promotes APL-initiating cell self-renewal. Recent studies have shown that PML-RARα also affects PML sumoylation and PML nuclear bodies assembly, which regulate stem cell self-renewal [2]. Combined retinoic acid (RA) with arsenic trioxide (ATO) dramatically improves the prognosis of APL patients and cure most patients. Mechanistically both agents directly target the PML-RARα-mediated transcriptional repression and protein stability which induce promyelocyte differentiation and eliminate leukemia-initiating cells. At the molecular level, RA and ATO bind to the RARα moiety or PML moiety of PNL-RARα respectively. ATO further induces PML/PML-RARα sumoylation and sumoylated PML/ PML-RARα interacts with E3 ubiquitin-ligase RNF4, ubiquitin, proteasomes and other sumoylated proteins, and recruits them onto PML nuclear bodies (PML-NBs), where ATO integrates the ubiquitination and degradation of PML-RARα/PML. Despite that combination of RA and ATO makes APL highly curable, relapsed and refractory APL still occur among all prognostic subgroups of APL patients. Therefore, searching for PPIs modulators promoting PML-RARα degradation, based on these two novel agents, may bring about new therapeutic options for APL therapy.Indeed, we recently report that TRIB3, a member of pseudokinase family, promotes APL progression through stabilization of the oncoprotein PML-RARα and inhibition of p53-mediated senescence [3]. TRIB3 acts as a member of tribbles homolog family that are fundamental regulators of cell cycle, differentiation, metabolism, proliferation, and cell stress, and is involved in chronic inflammatory and malignant disease through their interactions with intracellular signaling and functional proteins [4]. Our previous study revealed that TRIB3 promoted cancer development and progression by interacting with the signaling molecule SMAD3 or a selective autophagy receptor p62/SQSTM1 [5,6]. An α-helical peptide, which disturbs the interaction of TRIB3 and p62, displays an effective activation of autophagic flux, and significantly suppresses tumor growth and metastasis. In our current study, we find that t...

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