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| 1 | Striatins and STRIPAK complex partners in clinical outcomes of patients with breast cancer and responses to drug treatment显示文摘Objective: Striatins(STRNs) family, which contains three multi-domain scaffolding proteins, are cornerstones of the striatins interacting phosphatase and kinase(STRIPAK) complex. Although the role of the STRIPAK complex in cancer has become recognized in recent years, its clinical significance in breast cancer has not been fully established.Methods: Using a freshly frozen breast cancer tissue cohort containing both cancerous and adjacent normal mammary tissues, we quantitatively evaluated the transcript-level expression of all members within the STRIPAK complex along with some key interacting and regulatory proteins of STRNs. The expression profile of each molecule and the integrated pattern of the complex members were assessed against the clinical-pathological factors of the patients. The Cancer Genome Atlas(TCGA) dataset was used to evaluate the breast cancer patients’ response to chemotherapies. Four human breast cancer cell lines, MDA-MB-231, MDA-MB-361, MCF-7, and SKBR-3, were subsequently adopted for in vitro work.Results: Here we found that high-level expressions of STRIP2, calmodulin, CCM3, MINK1 and SLMAP were respectively associated with shorter overall survival(OS) of patients. Although the similar pattern observed for STRN3, STRN4 and a contrary pattern observed for PPP2CA, PPP2CB and PPPR1A were not significant, the integrated expression profile of STRNs group and PPP2 group members constitutes a highly significant prognostic indicator for OS [P<0.001, hazard ratio(HR)=2.04, 95% confidence interval(95% CI), 1.36-3.07] and disease-free survival(DFS)(P=0.003, HR=1.40, 95% CI, 1.12-1.75). Reduced expression of STRN3 has an influence on the biological functions including adhesiveness and migration. In line with our clinical findings, the breast cancer cells responded to STRN3 knockdown with changes in their chemo-sensitivity, of which the response is also breast cancer subtype dependent.Conclusions: Our results suggest a possible role of the STRIPAK complex in breast cancer development and prognosis. Among the members, the expression profile of STRN3 presents a valuable factor for assessing patients’ responses to drug treatment. | Amber Xinyu Li Jimmy Jianyuan Zeng Tracey A Martin Lin Ye Fiona Ruge Andrew J Sanders Elyas Khan QPing Dou Eleri Davies Wen G Jiang | 2023 | Chinese Journal of Cancer Research2023，35，4： | 0 |
| 2 | Bilirubin inhibits the anticancer activity of sorafenib by blocking MCL-1 degradation in hepatocellular carcinoma cells显示文摘Objective:Sorafenib is a first-line drug for advanced hepatocellular carcinoma(HCC).Unfortunately,most patients with HCC do not respond to sorafenib,mainly because of the frequent development of drug resistance.Bilirubin is an end metabolite of heme catabolism and an indicator of liver function,but its direct role in regulating the anticancer activity of sorafenib in HCC cells is unclear.In the current study,we aimed to investigate the mechanism of action of bilirubin in sorafenib-mediated tumor suppression in HCC.Methods:A retrospective observational cohort of 100 patients receiving sorafenib was conducted to evaluate the potential role of bilirubin in predicting the prognosis of patients with HCC.Human HCC cell lines were treated with sorafenib in the absence or presence of bilirubin,and cell proliferation,apoptosis,and signaling pathways were assayed.The antagonistic effect of bilirubin toward sorafenib was assessed in nude mice bearing HCC xenografts.Results:Serum levels of bilirubin(including total,direct,and indirect bilirubin)negatively correlated with the overall survival of patients with HCC treated with sorafenib(P<0.05).Both in vitro and in vivo analyses demonstrated that bilirubin significantly abrogated sorafenib-mediated proliferation inhibition and apoptosis induction in HCC cells(P<0.05).Mechanically,bilirubin inhibited sorafenib-induced activation of GSK-3βand subsequent downstream MCL-1 degradation.Conclusions:Our study provides experimental evidence of the antagonistic effect of bilirubin toward sorafenib-mediated anticancer activity in HCC,and it suggests that bilirubin could be used to predict the efficacy of sorafenib treatment. | Leyi Yao Qian Zhao Ding Yan Ziying Lei Yali Hao Jinghong Chen Qian Xue Xiaofen Li Qingtian Huang Daolin Tang QPing Dou Xin Chen Jinbao Liu | 2022 | Cancer Biology & Medicine2022，19，7： | 0 |
| 3 | Pharmacological characterization of a novel metal-based proteasome inhibitor Na-AuPT for cancer treatment显示文摘The ubiquitin-proteasome system(UPS)is essential for maintaining cell homeostasis by orchestrating the protein degradation,but is impaired in various diseases,including cancers.Several proteasome inhibitors,such as bortezomib,are currently used in cancer treatment,but associated toxicity limits their widespread application.Recently metal complex-based drugs have attracted great attention in tumor therapy;however,their application is hindered by low water-solubility and poor absorbency.Herein,we synthesized a new type of gold(I)complex named Na-AuPT,and further characterized its anticancer activity.Na-AuPT is highly water-soluble(6 mg/mL),and it was able to potently inhibit growth of a panel of 11 cancer cell lines(A549,SMMC7721,H460,HepG2,BEL7402,LNCap,PC3,MGC-803,SGC-7901,U266,and K562).In A549 and SMMC7721 cells,Na-AuPT(in a range of 2.5–20μM)inhibited the UPS function in a dose-dependent fashion by targeting and inhibiting both 20 S proteasomal proteolytic peptidases and 19 S proteasomal deubiquitinases.Furthermore,Na-AuPT induced caspase-dependent apoptosis in A549 and SMMC7721 cells,which was prevented by the metal chelator EDTA.Administration of Na-AuPT(40 mg·kg^(−1)·d^(−1),ip)in nude mice bearing A549 or SMMC7721 xenografts significantly inhibited the tumor growth in vivo,accompanied by increased levels of total ubiquitinated proteins,cleaved caspase 3 and Bax protein in tumor tissue.Moreover,Na-AuPT induced cell death of primary mononuclear cells from 5 patients with acute myeloid leukemia ex vivo with an average IC_(50) value of 2.46μM.We conclude that Na-AuPT is a novel metal-based proteasome inhibitor that may hold great potential for cancer therapy. | Da-cai Xu Li Yang Pei-quan Zhang Ding Yan Qian Xue Qing-tian Huang Xiao-fen Li Ya-li Hao Dao-lin Tang QPing Dou Xin Chen Jin-bao Liu | 2022 | Acta Pharmacologica Sinica2022，43，8： | 0 |
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