Tumorigenic conversion of p53-deficient colon epithelial cells by an activated Ki-ras gene.

Sevignani, Cinzia; Włodarski, Paweł; Kirillova, J; Mercer, W E; Danielson, Kg; Iozzo, RV; Calabretta, Bruno

doi:10.1172/jci919

Cited by 35 publications

(26 citation statements)

References 26 publications

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“…1a). We also observed that detachment promotes Chk2 upregulation in nonmalignant anoikis-susceptible mouse colonocytes 17 ( Figs. 1b and 1c), another intestinal epithelium-derived cell line that we frequently utilize in our studies on anoikis.…”

Section: Detachment Of Intestinal Epithelial Cells From the Ecm Triggsupporting

confidence: 63%

Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells

Berezkin

Wang

Zagryazhskaya

et al. 2011

Intl Journal of Cancer

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Resistance of carcinoma cells to anoikis, apoptosis that is normally induced by detachment of nonmalignant epithelial cells from the extracellular matrix, is thought to be critical for carcinoma progression. Molecular mechanisms that control anoikis of nonmalignant and cancer cells are understood poorly. In an effort to understand them we found that detachment of nonmalignant intestinal epithelial cells triggers upregulation of Chk2, a pro-apoptotic protein kinase that has never been implicated in anoikis and has been thought to kill cells mainly under the conditions compromising genome integrity. We found that enforced downregulation of Chk2 protects intestinal epithelial cells from anoikis. Chk2 can kill cells by stabilizing p53 tumor suppressor protein or via p53-independent mechanisms, and we established that Chk2-mediated anoikis of intestinal epithelial cells is p53-independent. We further found that, unlike nonmalignant intestinal epithelial cells whose anoikis is triggered by detachment-induced Chk2 upregulation, intestinal epithelial cells carrying oncogenic ras, a known inhibitor of anoikis, remain anoikis-resistant in response to enforced Chk2 upregulation. By contrast, drugs, such as topoisomerase I inhibitors, that can kill cells via Chk2-indpendent mechanisms, efficiently triggered anoikis of rastransformed cells. Thus, oncogenic ras can prevent Chk2 from triggering anoikis even when levels of this protein kinase are elevated in cancer cells, and the use of therapeutic agents that kill cells in a Chk-2-independent, rather than Chk-2-dependent, manner could represent an efficient strategy for overcoming ras-induced anoikis resistance of these cells. We conclude that Chk-2 is an important novel component of anoikis-promoting machinery of intestinal epithelial cells.

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Section: Detachment Of Intestinal Epithelial Cells From the Ecm Triggsupporting

confidence: 63%

Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells

Berezkin

Wang

Zagryazhskaya

et al. 2011

Intl Journal of Cancer

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“…1D, the weights of these abortive tumors did not exceed 15 mg, ϳ10% of the neoplasms from uninfected mice. To demonstrate that this inhibitory effect is applicable to other neoplastic cells, we performed the same experiment with murine colonocytes transformed in vitro by the Ki-Ras2 oncogene (12), which bears the nonimmunogenic G-to-V mutation (13,14). These cells are normally tumorigenic, but in infected mice formed only small masses whose average weight did not exceed 30 mg (Fig.…”

Section: Resultsmentioning

confidence: 99%

Cutting Edge: Systemic Inhibition of Angiogenesis Underlies Resistance to Tumors During Acute Toxoplasmosis

Hunter

Gee

et al. 2001

The Journal of Immunology

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The ability of various infections to suppress neoplastic growth has been well documented. This phenomenon has been traditionally attributed to infection-induced concomitant, cell-mediated antitumor immunity. We found that infection with Toxoplasma gondii effectively blocked neoplastic growth of a nonimmunogenic B16.F10 melanoma. Moreover, this effect was independent of cytotoxic T or NK cells, production of NO by macrophages, or the function of the cytokines IL-12 and TNF-α. These findings suggested that antitumor cytotoxicity was not the primary mechanism of resistance. However, infection was accompanied by strong, systemic suppression of angiogenesis, both in a model system and inside the nascent tumor. This suppression resulted in severe hypoxia and avascular necrosis that are incompatible with progressive neoplastic growth. Our results identify the suppression of tumor neovascularization as a novel mechanism critical for infection-induced resistance to tumors.

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“…In fact, the only methodology to date for the consistent isolation of murine colonocyte epithelial cells requires genetic deletion of p53 from the starting tissues (31). However, the HCT116-derived human cell lines contain wild-type p53 and have been consistently used for studies involving normal p53 function(s).…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide–Donating Aspirin Derivatives Suppress Microsatellite Instability in Mismatch Repair–Deficient and Hereditary Nonpolyposis Colorectal Cancer Cells

et al. 2007

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Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) are an emergent class of pharmaceutical derivatives with promising utility as cancer chemopreventive agents. Aspirin and sulindac have been shown to be effective in selecting for cells with reduced microsatellite instability (MSI) that is inherent in mismatch repair (MMR)-deficient hereditary nonpolyposis colorectal cancer (HNPCC) cells. The effect of NO-NSAIDs on MSI in MMR-deficient HNPCC cells is unknown. Here, we have examined genetically defined MMRdeficient murine embryo fibroblasts, murine colonocytes, and isogenic human HNPCC tumor cell lines treated with acetylsalicylic acid (aspirin; ASA) and three isomeric derivatives of NO-aspirin (NO-ASA). The MSI profiles were determined and compared with the Bethesda Criteria. We found that the ASA-and NO-ASA-treated MMR-deficient cell lines displayed a dose-dependent suppression of MSI that appeared as early as 8 weeks and gradually increased to include up to 67% of the microsatellite sequences examined after 19 to 20 weeks of continuous treatment. Residual resistance to microsatellite stabilization was largely confined to mononucleotide repeat sequences. Control (MMR-proficient) cells showed no changes in microsatellite status with or without treatment. The relative dose-dependent stabilization selection was: ortho-NO-ASA % para-NO-ASA > meta-NO-ASA J ASA. Moreover, the doses required for stabilization by the orthoand para-NO-ASA were 300-to 3,000-fold lower than ASA. These results suggest that NO-ASA derivatives may be more effective at suppressing MSI in MMR-deficient cell lines than ASA and should be considered for chemopreventive trials with HNPCC carriers. [Cancer Res 2007;67(22):10966-75]

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Tumorigenic conversion of p53-deficient colon epithelial cells by an activated Ki-ras gene.

Cited by 35 publications

References 26 publications

Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells

Tumor suppressor protein kinase Chk2 is a mediator of anoikis of intestinal epithelial cells

Cutting Edge: Systemic Inhibition of Angiogenesis Underlies Resistance to Tumors During Acute Toxoplasmosis

Nitric Oxide–Donating Aspirin Derivatives Suppress Microsatellite Instability in Mismatch Repair–Deficient and Hereditary Nonpolyposis Colorectal Cancer Cells

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