Tumour maintenance is mediated by eNOS

Lim, Kian-Huat; Ancrile, Brooke B.; Kashatus, David F.; Counter, Christopher M.

doi:10.1038/nature06778

Cited by 284 publications

(275 citation statements)

References 36 publications

(48 reference statements)

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“…Itoh et al showed that Akt activation plays an important role during the progression of CRC by enhancement of cell proliferation activity and the blocking of apoptosis [40]. In addition, endothelial nitric oxide synthase (eNOS), a downstream target of Akt, has been shown to be important in tumorigenesis, including colorectal carcinogenesis [41,42]. The eNOS polymorphisms in relation to colorectal cancer risk were also investigated [42].…”

Section: Discussionmentioning

confidence: 99%

Circulating levels of novel adipocytokines in patients with colorectal cancer

et al. 2013

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a b s t r a c tObjective: Adipocytokines have been reported to contribute to the pathogenesis of colorectal cancer (CRC). The aim of this matched case-control study was to explore circulating novel adipocytokines, such as serum visfatin, omentin-1 and vaspin levels in patients with CRC. Method: Serum visfatin, omentin-1, and vaspin levels were measured in 69 subjects (39 patients with colorectal cancer and 30 age-and sex-matched healthy controls) using enzyme-linked immunosorbent assay (ELISA) methods. Results: Compared with the controls, patients with CRC had significantly higher circulating omentin-1 (203.23 vs 9.12 ng/ml, p < 0.0001) visfatin (4.03 vs 2.01 ng/ml, p < 0.0001) and vaspin (0.54 vs 0.31 ng/ ml, p = 0.015) levels. After adjustment for covariates (age and body mass index), patients with CRC had significantly higher serum omentin-1 (p < 0.0001), visfatin (p < 0.0001), and vaspin (p = 0.040) levels than the control group. Furthermore, the results did not change when age and waist-to-hip ratio were considered as covariates in the general linear models. Conclusions: The observed higher levels of omentin-1, visfatin, and vaspin in patients with CRC, independent of measures of obesity, suggest that these adipocytokines may have a potential role in the development of CRC through mechanisms other than the indirect mechanisms that are active in the association between obesity and CRC.

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Section: Discussionmentioning

confidence: 99%

Circulating levels of novel adipocytokines in patients with colorectal cancer

et al. 2013

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“…NOS activity has been detected in various tumors and has been associated with tumor grade and proliferation rate. A recent study showed that eNOS-mediated Ras activation by S-nitrosylation was important for initiation and maintenance of tumor (32). c-Src is known to be activated in several cancers, and there is convincing evidence that increased Src activity is associated with more invasive and aggressive phenotypes (33).…”

Section: Discussionmentioning

confidence: 99%

“…Immunoprecipitates were washed and incubated in kinase buffer (10 mM Tris-HCl, 5 mM MgCl 2 , pH 7.4) with [␥ 32 -P]ATP and 1 g of casein at 30°C for 20 min in the presence or absence of SNAP. SDS sample buffer was added to the reaction mixtures and then subjected to electrophoresis and analyzed by the BAS 2000 system.…”

Section: Methodsmentioning

confidence: 99%

S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

Rahman

Senga

Ito

et al. 2010

Journal of Biological Chemistry

101

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“…2 B and C) indicated that H-Ras G12V escaped from the regulation by Sos. However, Sos inhibition might be effective for some cancer types, considering that the function of wild-type Ras is required for the growth of tumors carrying the activated ras oncogene (21).…”

Section: Discussionmentioning

confidence: 99%

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras–effector interaction

Shima

Yoshikawa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

271

269

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Mutational activation of the Ras oncogene products (H-Ras, K-Ras, and N-Ras) is frequently observed in human cancers, making them promising anticancer drug targets. Nonetheless, no effective strategy has been available for the development of Ras inhibitors, partly owing to the absence of well-defined surface pockets suitable for drug binding. Only recently, such pockets have been found in the crystal structures of a unique conformation of Ras⋅GTP. Here we report the successful development of small-molecule Ras inhibitors by an in silico screen targeting a pocket found in the crystal structure of M-Ras⋅GTP carrying an H-Ras–type substitution P40D. The selected compound Kobe0065 and its analog Kobe2602 exhibit inhibitory activity toward H-Ras⋅GTP-c-Raf-1 binding both in vivo and in vitro. They effectively inhibit both anchorage-dependent and -independent growth and induce apoptosis of H- ras G12V –transformed NIH 3T3 cells, which is accompanied by down-regulation of downstream molecules such as MEK/ERK, Akt, and RalA as well as an upstream molecule, Son of sevenless. Moreover, they exhibit antitumor activity on a xenograft of human colon carcinoma SW480 cells carrying the K-ras G12V gene by oral administration. The NMR structure of a complex of the compound with H-Ras⋅GTP T35S , exclusively adopting the unique conformation, confirms its insertion into one of the surface pockets and provides a molecular basis for binding inhibition toward multiple Ras⋅GTP-interacting molecules. This study proves the effectiveness of our strategy for structure-based drug design to target Ras⋅GTP, and the resulting Kobe0065-family compounds may serve as a scaffold for the development of Ras inhibitors with higher potency and specificity.

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Tumour maintenance is mediated by eNOS

Cited by 284 publications

References 36 publications

Circulating levels of novel adipocytokines in patients with colorectal cancer

Circulating levels of novel adipocytokines in patients with colorectal cancer

S-Nitrosylation at Cysteine 498 of c-Src Tyrosine Kinase Regulates Nitric Oxide-mediated Cell Invasion

In silico discovery of small-molecule Ras inhibitors that display antitumor activity by blocking the Ras–effector interaction

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