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Novel signaling axis for ROS generation during K-Ras-induced cellular transformation.

ABSTRACT: Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasma membrane. Of note, PKC?, when it was activated by PDPK1, directly bound to the SH3-N domain of p47(phox) and catalyzed the phosphorylation on Ser348 and Ser473 residues of p47(phox) C-terminal in a K-Ras-dependent manner, finally leading to its membrane translocation. Notably, oncogenic K-Ras activated all MAPKs (JNK, ERK and p38); however, only p38 was involved in p47(phox)-NOX1-dependent ROS generation and consequent transformation. Importantly, K-Ras-induced activation of p38 led to an activation of PDPK1, which then signals through PKC?, p47(phox) and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKC?, p47(phox) or NOX1 effectively blocked K-Ras-induced ROS generation, anchorage-independent colony formation and tumor formation. Taken together, our findings demonstrated that oncogenic K-Ras activates the signaling cascade p38/PDPK1/PKC?/p47(phox)/NOX1 for ROS generation and consequent malignant cellular transformation.

SUBMITTER: Park MT

PROVIDER: S-EPMC4085525 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Novel signaling axis for ROS generation during K-Ras-induced cellular transformation.

Park M-T MT Kim M-J MJ Suh Y Y Kim R-K RK Kim H H Lim E-J EJ Yoo K-C KC Lee G-H GH Kim Y-H YH Hwang S-G SG Yi J-M JM Lee S-J SJ

Cell death and differentiation 20140314 8

Reactive oxygen species (ROS) are well known to be involved in oncogene-mediated cellular transformation. However, the regulatory mechanisms underlying ROS generation in oncogene-transformed cells are unclear. In the present study, we found that oncogenic K-Ras induces ROS generation through activation of NADPH oxidase 1 (NOX1), which is a critical regulator for the K-Ras-induced cellular transformation. NOX1 was activated by K-Ras-dependent translocation of p47(phox), a subunit of NOX1 to plasm ...[more]

PMID: 24632950

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Project description:IntroductionTyrosine phosphorylated signal transducer and activator of transcription 3 (pStat3) is present in numerous cancers and is required for mediating tumorigenesis. Autocrine and paracrine interleukin (IL)-6 signaling is the principal mechanism by which Stat3 is persistently phosphorylated in epithelial tumors including breast, lung, colon and gastric cancer. The Ras oncogene mediates cellular transformation without evidence of pStat3 in cultured cells. Recently, however non-tyrosine phosphorylated Stat3 was shown to have a transcriptional activating function, a role in mitochondrial function and to mediate cell migration.. Here we examined the role of Stat3 in Ras mediated transformation.MethodsHa-rasV12 transformed mammary epithelial cells (MCF10A) cells were transduced with a Stat3shRNA, IL-6shRNA and/or treated with inhibitors of Janus kinases (JAKs) to examine the role of the IL-6 signaling pathway in Ras mediated invasion and tumorigenesis.ResultsCellular migration, invasion, anchorage independent growth and tumorigenesis were largely abrogated in the Stat3-reduced cells compared to control cells. Analysis of MCF10A-Ras tumors revealed high levels of pStat3 and interleukin-6. Tumors derived from transgenic MMTV-K-Ras mice were also found to express pStat3 and IL-6. MCF10A-Ras cells, when grown in a three-dimensional Matrigel culture system revealed the appearance of the junctional protein E-Cadherin as a consequence of reducing Stat3 levels or inhibiting Stat3 activity. Decreasing IL-6 levels in the MCF10A-Ras cells abrogated tumorigenesis and reduced cell migration. By isolating Ras-expressing primary tumors and serially passaging these cells in two-dimensional culture led to a decrease in IL-6 and pStat3 levels with the reappearance of E-Cadherin.ConclusionsThe cellular and environmental context can lead to differential IL-6/pStat3 signaling and a dependency on this cytokine and transcription factor for migration, invasion and tumorigenesis.

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Novel signaling axis for ROS generation during K-Ras-induced cellular transformation.

Publications

Novel signaling axis for ROS generation during K-Ras-induced cellular transformation.

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