Antagonizing SET Augments the Effects of Radiation Therapy in Hepatocellular Carcinoma through Reactivation of PP2A-Mediated Akt Downregulation

Abstract

Increasing evidence suggests that SET functions as an oncoprotein and promotes cancer survival and therapeutic resistance. However, whether SET affects radiation therapy (RT)-mediated anticancer effects has not yet been explored. We investigated the impact of SET on RT sensitivity in hepatocellular carcinoma (HCC). Using colony and hepatosphere formation assays, we found that RT-induced proliferative inhibition was critically associated with SET expression. We next tested a novel SET antagonist, N-(3-ethynylphenyl)-6,7-dimethoxy-N-(4-phenoxyphenyl) quinazoline-2,4-diamine (EMQA), in combination with RT. We showed that additive use of EMQA significantly enhanced the effects of RT against HCC in vitro and in vivo. Notably, compared with mice receiving either RT or EMQA alone, the growth of PLC5 xenografted tumor in mice receiving RT plus EMQA was significantly reduced without compromising treatment tolerability. Furthermore, we proved that antagonizing SET to restore protein phosphatase 2A-mediated phospho-Akt (p-AKT) downregulation was responsible for the synergism between EMQA and RT. Our data demonstrate a new oncogenic property of SET and provide preclinical evidence that combining a SET antagonist and RT may be effective for treatment of HCC. Further investigation is warranted to validate the clinical relevance of this approach.

Cyclin-dependent kinase 1-mediated phosphorylation of SET at serine 7 is essential for its oncogenic activity

“…8b). Consistent with previous studies 51 , Akt activity (revealed by phosphorylation at T308 and S473) was greatly decreased upon SET inhibition in RKO cells (Fig. 8b).…”

Cucurbitacin B Induces the Lysosomal Degradation of EGFR and Suppresses the CIP2A/PP2A/Akt Signaling Axis in Gefitinib-Resistant Non-Small Cell Lung Cancer

“…Mutations leading to the abnormal expression of PP2A scaffolds and regulatory subunits are common in many human cancers [16]. Therefore, based on its tumor suppressive properties, the reactivation of PP2A is a potential strategy for cancer treatment [17,18]. Targeting the oncoprotein CIP2A is an important strategy to reactivate PP2A to treat cancer.…”

Bi-Functional Peptides as a New Therapeutic Tool for Hepatocellular Carcinoma

“…The oncogenic role of SET in HCC was first suggested by Fukukawa et al [ 70 ] who demonstrated that SET expression is highly upregulated in progressive HCC, indicating that SET may be involved in HCC development. Furthermore, SET activity is associated with development of resistance to chemotherapies [ 71 , 72 , 73 ]. Results obtained with patient primary cells support the oncogenic role of SET in HCC, suggesting that SET may serve as a novel biomarker to guide treatment in patients with HCC [ 69 ].…”