title: Aurora kinase A regulates Survivin stability through targeting FBXL7 in gastric cancer drug resistance and prognosis.
abstract: Aurora kinase A (AURKA) has been implicated in the regulation of cell cycle progression, mitosis and a key number of oncogenic signaling pathways in various malignancies. However, little is known about its role in gastric cancer prognosis and genotoxic resistance. Here we found that AURKA was highly overexpressed in gastric cancer and inversely correlated with disease prognosis. Overexpression of AURKA exacerbated gastric cancer drug resistance through upregulating the expression of the anti-apoptotic protein Survivin. Conversely, we demonstrated that AURKA depletion caused a decrease in Survivin protein levels by increasing its ubiquitylation and degradation. Mass spectrometric analysis revealed that upon AURKA depletion, Survivin bound to the FBXL7 E3 ubiquitin ligase, which induced ubiquitin-proteasome degradation of Survivin. In addition, we showed that AURKA regulated FBXL7 both at the levels of transcription and translation. Moreover, proteomic analysis of nuclear AURKA-interacting proteins identified Forkhead box protein P1 (FOXP1). We next showed that AURKA was required for FBXL7 transcription and that AURKA negatively regulated FOXP1-mediated FBXL7 expression. The physiological relevance of the regulation of Survivin by AURKA through the FOXP1-FBXL7 axis was further underscored by the significant positive correlations between AURKA and Survivin expression in gastric cancer patient samples. Moreover, the AURKA depletion or kinase inhibition-induced apoptotic cell death could be reversed by Survivin ectopic overexpression, further supporting that AURKA regulated Survivin to enhance drug resistance. In agreement, inhibition of AURKA synergistically enhanced the cytotoxic effect of DNA-damaging agents in cancer cells by suppressing Survivin expression. Taken together, our data suggest that AURKA restricts Survivin ubiquitylation and degradation in gastric cancer to promote drug resistance and hence the AURKA-Survivin axis can be targeted to promote the efficacy of DNA-damaging agents in gastric cancer.
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: M
authors.initials: M
authors.lastname: Kamran
authors.affiliation: Department of Hematology, The Third Affiliated Hospital; Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Long
authors.affiliation: State key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine/Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China.
authors.forename: D
authors.initials: D
authors.lastname: Xu
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: S-S
authors.initials: SS
authors.lastname: Lv
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: C-L
authors.initials: CL
authors.lastname: Wang
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Surgery and Cancer, Imperial College London, London, UK.
authors.forename: E W-F
authors.initials: EW
authors.lastname: Lam
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian/State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.|Department of Hematology, The Third Affiliated Hospital; Institute of Hematology, Sun Yat-sen University, Guangzhou, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Liu