SET antagonist enhances the chemosensitivity of non-small cell lung cancer cells by reactivating protein phosphatase 2A

Abstract

SET is known as a potent PP2A inhibitor, however, its oncogenic role including its tumorigenic potential and involvement in the development of chemoresistance in non-small cell lung cancer (NSCLC) has not yet been fully discussed. In present study, we investigated the oncogenic role of SET by SET-knockdown and showed that SET silencing impaired cell growth rate, colony formation and tumor sphere formation in A549 cells. Notably, silencing SET enhanced the pro-apoptotic effects of paclitaxel, while ectopic expression of SET diminished the sensitivity of NSCLC cells to paclitaxel. Since the SET protein was shown to affect chemosensitivity, we next examined whether combining a novel SET antagonist, EMQA, sensitized NSCLC cells to paclitaxel. Both the in vitro and in vivo experiments suggested that EMQA and paclitaxel combination treatment was synergistic. Importantly, we found that downregulating p-Akt by inhibiting SET-mediated protein phosphatase 2A (PP2A) inactivation determined the pro-apoptotic effects of EMQA and paclitaxel combination treatment. To dissect the critical site for EMQA functioning, we generated several truncated SET proteins. By analysis of the effects of EMQA on the binding affinities of different truncated SET proteins to PP2A-catalytic subunits, we revealed that the 227–277 amino-acid sequence is critical for EMQA-induced SET inhibition. Our findings demonstrate the critical role of SET in NSCLC, particularly in the development of chemoresistance. The synergistic effects of paclitaxel and the SET antagonist shown in current study encourage further validation of the clinical potential of this combination.

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

“…More interestingly, our group and others have found that the activity of SET is associated with the development of resistance to standard anticancer drugs, namely chemotherapies or target therapies, in various malignant diseases (Agarwal et al, 2014;Cristobal et al, 2015;Hung et al, 2015Hung et al, , 2016Zhang et al, 2015). For example, ectopic expression of SET diminished the effects of paclitaxel against non-small cell lung cancer (Hung et al, 2015) and oxaliplatin against colon cancer (Cristobal et al, 2015). The present study elaborated the impact of SET dysregulation in relation to RT, another important anticancer modality, thus adding to current knowledge.…”

“…SET is a novel oncoprotein that affects the behavior of cancer cells in multiple ways (von Lindern et al, 1992;Al-Murrani et al, 1999;Fan et al, 2003;Arnaud et al, 2011;Switzer et al, 2011;Hung et al, 2015Hung et al, , 2016. Initially, set gene was identified as a novel fusion partner of a putative oncogene, can, in a patient with acute undifferentiated leukemia (von Lindern et al, 1992;Adachi et al, 1994).…”

“…Later, Dr. Damuni's group purified this oncoprotein from bovine kidney and characterized its function as a potent inhibitor of PP2A (Li et al, 1995). To date, aberrant expression of SET protein has been reported in patients with various types of malignancies, such as leukemia, sarcoma, and tumors of breast, colon, liver, and lung (Li et al, 1996;Carlson et al, 1998;Chae et al, 2012;Cristobal et al, 2012Cristobal et al, , 2015Hung et al, 2015Hung et al, , 2016Liu et al, 2015). The oncogenic role of SET in HCC was first suggested by Fukukawa et al (2000).…”

Isoliensinine induces dephosphorylation of NF-κB p65 subunit at Ser536 via a PP2A-dependent mechanism in hepatocellular carcinoma cells: roles of impairing PP2A/I2PP2A interaction

“…These findings indicated that I2PP2A can be a direct target of isolie. In addition to isolie, other structurally unrelated chemicals also enhance the activity of PP2A via interfering with the binding between PP2A and I2PP2A [31, 32]. The molecular pathways underlying isolie-provoked p65 dephosphorylation at Ser536 and subsequent HCC cell apoptosis are schematically summarized in Figure 6.…”

Targeting PP2A in cancer: Combination therapies

“…Although multiple inhibitors of the downstream PI3K and MAPK signaling pathway have been developed, they have largely been unsuccessful in clinical trials due to high toxicity and limited efficacy [51, 52]. Since loss of PP2A regulatory subunits and overexpression of SET and CIP2A have all been reported in lung cancer [53-55], the Westermarck group investigated the role of PP2A suppression in driving resistance to kinase inhibitors in KRAS-driven lung cancer cell lines. This was done using a high-throughput drug screen in which two KRAS-driven NSCLC cell lines were treated with 230 different kinase inhibitors.…”