Blocking Oncogenic Ras Signaling for Cancer Therapy

Adjei, Alex A.

doi:10.1093/jnci/93.14.1062

Cited by 760 publications

(632 citation statements)

References 129 publications

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“…G12D), resulting in the change of the encoded amino acid from glycine (G) to aspartic acid (D). Activated Ras protein is known to directly interact with a number of distinct effectors to trigger downstream signaling pathways, including activation of the RAF/MEK/ERK, PI3K/AKT and RAL-GTP pathways, to impact cellular proliferation, apoptosis and neoplastic transformation (Vojtek and Der, 1998;Adjei, 2001). Despite years of intense effort, therapeutics targeted against oncogenic K-ras have failed to prolong patient survival in tumors harboring activated K-ras mutations (Karp et al, 2001;Doll et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

K-ras activation generates an inflammatory response in lung tumors

et al. 2005

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Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras G12D alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.

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Section: Introductionmentioning

confidence: 99%

K-ras activation generates an inflammatory response in lung tumors

et al. 2005

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“…Ras mutations are found in around 30% of all human malignancies, with K-Ras being the most frequently activated oncogene in cancer cells. 13,14 Notably, aberrant activation of Ras alone was found to be sufficient to transform mammary epithelial cells into malignant cells. Although the underlying mechanisms remain obscure, several lines of evidence suggested the functional role of ROS in Ras-induced cellular transformation.…”

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confidence: 99%

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

et al. 2014

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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, PKCd, 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 PKCd, p47 phox and NOX1. In agreement with the mechanism, inhibition of p38, PDPK1, PKCd, 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/PKCd/p47 phox /NOX1 for ROS generation and consequent malignant cellular transformation.

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“…Such mutations that change the protooncogene RAS to an active oncogene are found in approximately 30 to 50% of human tumors. [4][5][6][7][8] Ras has also been demonstrated to be important for both the genesis and maintenance of melanoma. For instance, in a doxycycline-inducible H-Ras V12G mouse melanoma model, withdrawal of doxycycline was demonstrated to result in histological regression of primary and implanted tumors accompanied by marked apoptosis of melanoma cells.…”

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confidence: 99%

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells

Eskandarpour¹,

Kiaii²,

Zhu³

et al. 2005

Intl Journal of Cancer

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The majority of human melanomas harbor activating mutations in either the BRAF or NRAS gene. To date, the role of oncogenic NRAS in melanoma remains poorly defined and no current therapies are directed at specifically suppressing oncogenic NRAS in human melanoma tumors. The aim of our study, therefore, was to investigate the effects of suppressing oncogenic NRAS in human melanoma cell lines in vitro. Using both small interfering RNAand plasmid based-RNA interference techniques, oncogenic NRAS was specifically suppressed in 2 human melanoma cell lines, 224 and BL, which harbor a codon 61 CAA (glutamine) to CGA (arginine) NRAS mutation. Suppression of oncogenic NRAS in these cell lines resulted in increased apoptosis. Furthermore, in 224 cells we demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and reduced expression of NF-kB and cyclin D1 in the N-Ras signaling pathway. In contrast, RNA interference directed at wild-type (WT) NRAS had no significant effect on apoptosis of 224 cells or 2 human melanoma cell lines (A375 and 397) containing WT NRAS but a codon 600 GTG (valine) to GAG (glutamate) mutation in BRAF. These data suggest that oncogenic NRAS is important for avoidance of apoptosis in melanomas that harbor the codon 61 NRAS mutation and emphasizes oncogenic NRAS as a therapeutic target in patients with tumors that harbor this mutation. ' 2005 Wiley-Liss, Inc.Key words: RNAi; melanoma; Ras; signal transduction; apoptosis Activation of Ras is a common molecular event in the etiology of human cancer. 1 The Ras proteins H-, K-and N-Ras are central regulators of cellular signal transduction processes leading to cell growth and differentiation. In the resting cell, Ras proteins are in the guanosine diphosphate (GDP)-bound inactive state. However, in response to receptor protein tyrosine kinases or other growth factor-dependent stimuli, these Ras proteins become activated by binding guanosine triphosphate (GTP). 2,3 Oncogenic mutations in codons 12, 13 and 61 of RAS genes prevent GTP hydrolysis, resulting in constitutively active Ras proteins. Such mutations that change the protooncogene RAS to an active oncogene are found in approximately 30 to 50% of human tumors. [4][5][6][7][8] Ras has also been demonstrated to be important for both the genesis and maintenance of melanoma. For instance, in a doxycycline-inducible H-Ras V12G mouse melanoma model, withdrawal of doxycycline was demonstrated to result in histological regression of primary and implanted tumors accompanied by marked apoptosis of melanoma cells. 9 Studies on melanoma tumors have confirmed that oncogenic activation of NRAS constitutes the predominant RAS alteration in cutaneous melanoma, with NRAS codon 61 mutations being the most common alterations and codon 12 and 13 mutations being less frequent. 6,7,10,11 In sporadic melanoma cases, the frequency of NRAS alterations reported varies in different studies. [12][13][14] In a study performed by our group, 28% of primary melanomas and 37% of metastatic tumo...

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Blocking Oncogenic Ras Signaling for Cancer Therapy

Cited by 760 publications

References 129 publications

K-ras activation generates an inflammatory response in lung tumors

K-ras activation generates an inflammatory response in lung tumors

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

Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells

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