Expression profile‑driven discovery of AURKA as a treatment target for liposarcoma

Abstract

Liposarcoma (LPS) is one of the most frequently reported type of soft-tissue sarcoma (STS). Well-differentiated (WD) LPS and dedifferentiated (DD) LPS are the two most common subtypes. Chemotherapy has been considered to be ineffective in LPS, and novel treatment agents are thus necessary. In this study, we reanalyzed two published microarray data sets of LPS. By comparing the top 50 upregulated genes in DD LPS in both sets of data, we identified 12 overlapping genes. Of note, the top five gene sets enriched in DD LPS in both sets of data were involved in cell cycle regulation. Among the 12 overlapping genes, aurora kinase A (AURKA) is a well-known gene involved in cell cycle regulation; we thus further investigated this gene. AURKA was significantly upregulated in DD LPS, compared with WD LPS. Among 40 cases of DD LPS in GSE30929, patients with high AURKA expression in tumors had significantly worse distant recurrence-free survival than those with low expression. In an in vitro model, MLN8237, an AURKA inhibitor, could inhibit AURKA in LPS cell lines with a resultant G2/M arrest. MLN8237 was also reported to exert a cytotoxic effect by inducing apoptosis in LPS cell lines. Furthermore, except for cisplatin, MLN8237 had a significantly synergistic effect with chemotherapy agents against LPS. MLN8237 induced cellular senescence in LPS cell lines with increased expression of DcR2, a senescence biomarker, and upregulated expression of cytokines associated with the senescence-associated secretory phenotype, including interleukin (IL)-1α, IL-6 and IL-8. Our study identified AURKA as a potential biomarker for predicting poor prognosis in LPS. The findings of the present study suggested the potential of AURKA as a therapeutic target in LPS cell line models, while the novel combination of AURKA inhibitors and chemotherapy requires further investigation.

Recent Advancement in Atypical Lipomatous Tumor Research

“…Aurora A and B kinases inhibition by RNAi and pharmacological treatment with a pan Aurora kinase inhibitor AMG 900 reduced tumor proliferation and cell survival in liposarcoma cell lines [96]. MLN8237, an Aurora A kinase inhibitor, showed G2/M phase cell cycle arrest and a cytotoxic effect leading to apoptosis of tumor cells with a significant synergistic effect with chemotherapy agents against LPS, except for cisplatin [97].…”

Comprehensive Analysis of Tumor-Infiltrating Immune Cells and Relevant Therapeutic Strategy in Esophageal Cancer

“…Besides, Liu et al pointed that PABPC4 likely played a role in the pathogenesis of colorectal cancer [57]. In various types of cancers, numerous studies have now documented a link between EIF4A3, SMC3, ESPL1, CDC25B, CCNA2, or AURKA and their response to therapy [58][59][60][61][62][63]. For the downregulation core gene THBS3, conversely, it was expressed at significantly 9 Disease Markers high levels in osteosarcoma, which was a predictor of worse OS at diagnosis [64].…”

Targeting AURKA in treatment of peritoneal tumor dissemination in gastrointestinal cancer

“…tumors regulates treatment resistance not only via tumor polyploidization, but also via expansion of impaired TAMs through GDF15 production. Some studies have also shown regulation of production of cytokines and chemokines by AURKA [ 25 , 26 ], although AURKA is a protein kinase mainly regulating cell cycle. However, locking AURKA with MLN8237 or siRNAs abrogates these adverse events, and successfully elicits anti-tumor immunity in the ascites models.…”