Ski Promotes Tumor Growth Through Abrogation of Transforming Growth Factor-β Signaling in Pancreatic Cancer

Heider, T. Ryan; Lyman, Suzanne; Schoonhoven, Robert; Behrns, Kevin E.

doi:10.1097/sla.0b013e318070cafa

Cited by 44 publications

(43 citation statements)

References 25 publications

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“…The oncogenic activity of Ski is primarily defined by its ability to promote anchorage-independent growth of chicken and quail embryo fibroblast when overexpressed (3). Consistent with this, Ski has been found to be expressed at high levels in human cancer cells derived from melanoma, esophageal cancer, colorectal cancer, pancreatic cancer, and leukemia (4)(5)(6)(7)(8). However, Ski may also contain an antitumorigenic activity.…”

Section: Introductionmentioning

confidence: 74%

“…Presently, the hypothesis that Ski behaves as an oncogene in human cells was supported by studies indicating that the level of Ski expression correlates with the progression of various human cancers, including leukemia, esophageal cancer, pancreatic cancer, and melanoma (4)(5)(6)(7)(8). Inversely, the antitumorigenic activity of Ski is also substantiated by the increased susceptibility of heterozygous Ski knockout mice to chemical carcinogens (9), by this study, by its chromosomal localization (10), and by a recent report showing that adenovirus-mediated overexpression of Ski in JygMC(A) mammary carcinoma cells reduced its metastatic potential in vivo (44).…”

Section: Discussionmentioning

confidence: 99%

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Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation

et al. 2008

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Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation

et al. 2008

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“…In addition, Ski regulates distinct cellular signaling pathways, including nuclear hormone receptors, Wnt/␤-catenin signaling, GATA1, PU.1, and retinoblastoma (RB) (2). Consistent with its oncogenic activity, Ski is overexpressed in many tumors, including melanoma (6), colorectal cancer (7), pancreatic cancer (8) esophageal cancer (9), gastric cancer (10), and leukemia (11). In addition, RNA interference (RNAi)-mediated silencing of Ski expression inhibits the tumorigenic properties of cancer cells (12).…”

mentioning

confidence: 99%

Suppression of p53 Activity through the Cooperative Action of Ski and Histone Deacetylase SIRT1

Inoue

Iemura

Natsume

et al. 2011

Journal of Biological Chemistry

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Ski was originally identified as an oncogene based on the fact that Ski overexpression transformed chicken and quail embryo fibroblasts. Consistent with these proposed oncogenic roles, Ski is overexpressed in various human tumors. However, whether and how Ski functions in mammalian tumorigenesis has not been fully investigated. Here, we show that Ski interacts with p53 and attenuates the biological functions of p53. Ski overexpression attenuated p53-dependent transactivation, whereas Ski knockdown enhanced the transcriptional activity of p53. Interestingly, Ski bound to the histone deacetylase SIRT1 and stabilized p53-SIRT1 interaction to promote p53 deacetylation, which subsequently decreased the DNA binding activity of p53. Consistent with the ability of Ski to inactivate p53, overexpressing Ski desensitized cells to genotoxic drugs and Nutlin-3, a small-molecule antagonist of Mdm2 that stabilizes p53 and activates the p53 pathway, whereas knocking down Ski increased the cellular sensitivity to these agents. These results indicate that Ski negatively regulates p53 and suggest that the p53-Ski-SIRT1 axis is an attractive target for cancer therapy.

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“…[5][6][7][8] Recent evidence has shown that expression of the oncoprotein, Ski, is evident in several human malignancies, and the magnitude of expression is correlated with tumor progression in melanoma and esophageal and colorectal cancers. [9][10][11][12][13] All these results suggest that Ski might act as a target of QYHJ treatment for pancreatic cancer. In this study, we established a human pancreatic cancer cell line SW1990 with low expression of Ski through the RNAi technique to evaluate the response to QYHJ treatment of SW1990 with different Ski expression statuses.…”

Section: Introductionmentioning

confidence: 98%

Ski Acts as Therapeutic Target of Qingyihuaji Formula in the Treatment of SW1990 Pancreatic Cancer

et al. 2010

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Background. Qingyihuaji formula (QYHJ) is a widely used herbal formula that has shown promising antitumor effect in the treatment of pancreatic cancer in the Cancer Hospital, Fudan University, Shanghai, China. Objective. This research was conducted to study whether Ski acts as a therapeutic target of QYHJ formula in the treatment of SW1990 pancreatic cancer. Methods. The expression changes of Ski mRNA and protein in SW1990 pancreatic cancer subcutaneously transplanted tumor treated with QYHJ were detected by real-time polymerase chain reaction and Western blot. Then, we established a stable transfection SW1990 cell with low expression of Ski through lentivirus-mediated RNA interference (RNAi) technique. The responses to QYHJ treatment on a subcutaneously transplanted tumor with different Ski expression statuses were evaluated. Finally, the effect of Ski downregulation on SW1990 cell biological behavior was also evaluated. Results. Expression of Ski mRNA and protein in SW1990 subcutaneously transplanted tumor decreased dramatically after the treatment with QYHJ. Stable transfection cells with low expression of Ski (SW1990/Ski RNAi) were created, and negative vector-transfected cells (SW1990/con RNAi) were used as controls. The tumor weight inhibitory rates of QYHJ on subcutaneously transplanted tumors formed by SW1990 or SW1990/con RNAi were 29.6% and 32.2%, respectively, whereas they were 16.0% to 17.8% when the tumors were formed by SW1990/Ski RNAi. Ski downregulation sensitized the response of SW1990 cells to TGF-b1-induced growth inhibition in vitro. Flow cytometric analyses revealed that the percentage of cells in the G1 phase increased from 40.4% to 62.9% when Ski was downregulated. The subcutaneously transplanted tumors formed by SW1990/Ski RNAi grew much more slowly than those formed by parental and control vector-transfected cells. Conclusion. Ski acts as therapeutic target of QYHJ in the treatment of SW1990 pancreatic cancer cells, and its expression status mediates different responses to QYHJ treatment.

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Ski Promotes Tumor Growth Through Abrogation of Transforming Growth Factor-β Signaling in Pancreatic Cancer

Abstract: Inhibition of Ski through RNA interference restored TGF-beta signaling and growth inhibition in vitro, and decreased tumor growth in vivo.

Cited by 44 publications

References 25 publications

Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation

Transforming Growth Factor-β Suppresses the Ability of Ski to Inhibit Tumor Metastasis by Inducing Its Degradation

Suppression of p53 Activity through the Cooperative Action of Ski and Histone Deacetylase SIRT1

Ski Acts as Therapeutic Target of Qingyihuaji Formula in the Treatment of SW1990 Pancreatic Cancer

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