Journal article
Regulation of pancreatic cancer growth by superoxide
Molecular carcinogenesis, Vol.52(7), pp.555-567
07/2013
DOI: 10.1002/mc.21891
PMCID: PMC3375391
PMID: 22392697
Abstract
K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O 2.-), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O 2.- were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O 2.-, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases that detoxify non-mitochondrial sources of O 2.-, and treatment with the small molecule O 2.- scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O 2.- produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth.
Details
- Title: Subtitle
- Regulation of pancreatic cancer growth by superoxide
- Creators
- Juan Du - Departments of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USAElke S NelsonAndrean L SimonsKristen E OlneyJustin C MoserHannah E SchrockBrett A WagnerGarry R BuettnerBrian J SmithMelissa L T TeohMing-Sound TsaoJoseph J Cullen
- Resource Type
- Journal article
- Publication Details
- Molecular carcinogenesis, Vol.52(7), pp.555-567
- DOI
- 10.1002/mc.21891
- PMID
- 22392697
- PMCID
- PMC3375391
- NLM abbreviation
- Mol Carcinog
- ISSN
- 0899-1987
- eISSN
- 1098-2744
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS R21 CA137230 / NCI NIH HHS T32 CA078586 / NCI NIH HHS CA115438 / NCI NIH HHS I01 BX001318 / BLRD VA R21 CA137230-01A1 / NCI NIH HHS R01 CA115438 / NCI NIH HHS R01 CA169046 / NCI NIH HHS CA137230 / NCI NIH HHS
- Language
- English
- Date published
- 07/2013
- Academic Unit
- Oral Pathology, Radiology and Medicine; Stead Family Department of Pediatrics; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Biostatistics; Surgery; Radiation Oncology; Holden Comprehensive Cancer Center; Hospital Medicine
- Record Identifier
- 9983997309002771
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