Radioresistance Induced by Oncogenic Transformation

Ling, C. Clifton; Endlich, Brian

doi:10.2307/3577713

Cited by 87 publications

(28 citation statements)

References 24 publications

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“…We and others have shown that transfection of rodent fibroblast cell lines with mutant H-Ras, N-Ras, and K-Ras results in decreased radiosensitivity (14,(50)(51)(52)(53) and that, conversely, loss of mutant K-ras alleles from DLD-1 human colon carcinoma or N-ras alleles from human HT1080 sarcoma cells leads to increased radiosensitivity (13). However, other studies have shown that transfection of Rat2 Figure 2.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

et al. 2005

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Activating K-ras mutations are found in f90% of pancreatic carcinomas and may contribute to the poor prognosis of these tumors. Because radiotherapy is frequently used in pancreatic cancer treatment, we assessed the contribution of oncogenic K-ras signaling to pancreatic cancer radiosensitivity. Seven human pancreatic carcinoma lines with activated K-ras and two cell lines with wild-type ras were used to examine clonogenic cell survival after Ras inhibition. Ras inhibition was accomplished by small interfering RNA (siRNA) knockdown of K-ras expression and by blocking Ras processing using a panel of prenyltransferase inhibitors of differing specificity for the two prenyltransferases that modify K-Ras. K-ras knockdown by siRNA or inhibition of prenyltransferase activity resulted in radiation sensitization in vitro and in vivo in tumors with oncogenic K-ras mutations. Inhibition of farnesyltransferase alone was sufficient to radiosensitize most K-ras mutant tumors, although K-Ras prenylation was not blocked. These results show that inhibition of activated K-Ras can promote radiation killing of pancreatic carcinoma in a superadditive manner. The finding that farnesyltransferase inhibition alone radiosensitizes tumors with K-ras mutations implies that a farnesyltransferase inhibitor-sensitive protein other than K-Ras may contribute to survival in the context of mutant K-ras. Farnesyltransferase inhibitors could therefore be of use as sensitizers for pancreatic carcinoma radiotherapy. (Cancer Res 2005; 65(18): 8433-41)

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Section: Discussionmentioning

confidence: 99%

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

et al. 2005

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“…Primers were designed to amplify the promoter CpG-rich region of PTEN, HIN1, RASSF1A, and RASSF2A gene by Methprimer. 6 The sequences of the primers are listed in Supplementary Table S1. All PCR reactions were done on PTC-100 thermocyclers (MJ Research) in a final volume of 25 AL containing bisulfite-modified DNA (2 AL), 1Â PCR buffer, 1.5 mmol/L MgCl 2 , 0.2 mmol/L deoxynucleotide triphosphate, 10 pmol of each primer, and 1 unit of Thermostar polymerase (ABgene).…”

Section: Methodsmentioning

confidence: 99%

Methylation of RASSF1A, RASSF2A, and HIN-1 Is Associated with Poor Outcome after Radiotherapy, but not Surgery, in Oral Squamous Cell Carcinoma

Huang

Huang²,

Chen³

et al. 2009

Clinical Cancer Research

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“…It was initially shown that the resistance of NIH3T3 cells to radiation could be enhanced by the expression of an activated H-Ras gene (2). This was later confirmed independently by several other groups using rodent cells, including rat embryo fibroblasts and rat rhabdomyosarcomas (3)(4)(5)(6), and human tumor cells, including an EJ Ras-transformed bladder carcinoma, DLD-1 colon carcinoma, and HT1080 fibrosarcoma (7,8). In agreement with such Ras-mediated radioresistance, several groups have reported that the blocking of Ras activity leads to an increase in radiosensitivity.…”

Section: Introductionmentioning

confidence: 62%

“…Oncogenic H-Ras has been shown to confer radioresistance to the majority of cell types examined (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). To identify the potential oncogenic H-Ras target genes that might be involved in the oncogenic H-Ras-mediated increased radioresistance, the effect of oncogenic H-Ras on the g-ray-induced cytotoxicity was initially reevaluated in the NIH3T3 cells.…”

Section: Resultsmentioning

confidence: 99%

Oncogenic H-Ras Up-regulates Expression of Ku80 to Protect Cells from γ-Ray Irradiation in NIH3T3 Cells

et al. 2005

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The Ras activation contributes to radioresistance, but the mechanism is unclear. This article shows that the expression of the dominant-positive H-Ras increased the Ku80 level, which is one of the key enzymes involved in repairing dsDNA breaks (DSB). After exposing the cells to ionizing radiation and analyzing them using an electrophoretic mobility shift assay and pulsed-field gel electrophoresis, it was found that activated H-Ras expression in NIH3T3 cells increases the DNAbinding activity of Ku80 and increases the DSB repair activity. Ku80 small interfering RNA expression was shown to reduce the oncogenic H-Ras-mediated increase in the DSBs and suppress the oncogenic H-Ras-mediated resistance of the cells to ;-ray irradiation, whereas Ku80 overexpression in the NIH3T3 cells significantly increased the radioresistance. These results suggest that the Ku80 expression induced by oncogenic H-Ras seems to play an important role in protecting cells against ;-ray irradiation. (Cancer Res 2005; 65(15): 6811-9)

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Radioresistance Induced by Oncogenic Transformation

Cited by 87 publications

References 24 publications

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

Pancreatic Cancer Cell Radiation Survival and Prenyltransferase Inhibition: The Role of K-Ras

Methylation of RASSF1A, RASSF2A, and HIN-1 Is Associated with Poor Outcome after Radiotherapy, but not Surgery, in Oral Squamous Cell Carcinoma

Oncogenic H-Ras Up-regulates Expression of Ku80 to Protect Cells from γ-Ray Irradiation in NIH3T3 Cells

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