Ras Family Signaling: Therapeutic Targeting

Cox, Adrienne D.; Der, Channing J.

doi:10.4161/cbt.306

Cited by 188 publications

(136 citation statements)

References 56 publications

(68 reference statements)

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“…6,8,21,28 As somatic mutations leading to the expression of oncogenic N-Ras are known to arise early in melanoma development and be maintained throughout melanoma progression, 11,29 oncogenic NRAS represents an attractive therapeutic target.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Interestingly, microarray analysis revealed that dominant-negative STAT1 mutant downregulates the expression of genes directly linked to tumorigenesis, like cyclin D2, which is upregulated in 80% of WTs (Rigolet et al, 2001), or thymosin b10, H-ras, cyclin-dependent kinase 10, which promote tumorigenesis in other organs (Santelli et al, 1999;Cox and Der, 2002;Nishiu et al, 2002), and genes that are involved in growth of the embryonic kidney, for example, Cux-1 (Vanden Heuvel et al, 1996). We observed serine-phosphorylated STAT1 in the developing rat kidney, and it may have a role in kidney development, for example, to promote progenitor cell survival before tissue vascularization.…”

Section: Stat1 Is a Prosurvival Factor In Wilms' Tumormentioning

confidence: 99%

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

et al. 2006

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Wilms' tumor (WT), one of the most common pediatric solid cancers, arises in the developing kidney as a result of genetic and epigenetic changes that lead to the abnormal proliferation and differentiation of the metanephric blastema. As activation of signal transducers and activators of transcription (STATs) plays an important role in the maintenance/growth and differentiation of the metanephric blastema, and constitutively activated STATs facilitate neoplastic behaviors of a variety of cancers, we hypothesized that dysregulation of STAT signaling may also contribute to WT pathogenesis. Accordingly, we evaluated STAT phosphorylation patterns in tumors and found that STAT1 was constitutively phosphorylated on serine 727 (S727) in 19 of 21 primary WT samples and two WT cell lines. An inactivating mutation of S727 to alanine reduced colony formation of WT cells in soft agar by more than 80% and induced apoptosis under conditions of growth stress. S727-phosphorylated STAT1 provided apoptotic resistance for WT cells via upregulation of expression of the heat-shock protein (HSP)27 and antiapoptotic protein myeloid cell leukemia (MCL)-1. The kinase responsible for STAT1 S727 phosphorylation in WT cells was identified based upon the use of selective inhibitors as protein kinase CK2, not p38, MAP-kinase kinase (MEK)1/2, phosphatidylinositol 3 0 -kinase, protein kinase C or Ca/calmodulindependent protein kinase II (CaMKII). The inhibition of CK2 blocked the anchorage-independent growth of WT cells and induced apoptosis under conditions of growth stress. Our findings suggest that serine-phosphorylated STAT1, as a downstream target of protein kinase CK2, plays a critical role in the pathogenesis of WT and possibly other neoplasms with similar STAT1 phosphorylation patterns.

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“…In fact, the different structures of the NRAS isoforms must be considered in the context of NRAS inhibitors. So far, direct and indirect targeting of the aberrantly activated RAS pathway has shown varying success in the clinic, which most likely is because of the complexity of RAS gene functions (22)(23)(24). However, as only amino acids 1-17 are shared among all five isoforms, pharmacologic approaches to specifically influence the expression of different isoforms (e.g., isoform 5 inhibition) might represent an option to enhance the effective targeting of this "undruggable" molecule (25).…”

Section: Protein Codementioning

confidence: 99%

NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation

Eisfeld

Schwind

Hoag

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The members of the rat sarcoma (RAS) gene family Kirsten rat sarcoma viral oncogene homolog, Harvey rat sarcoma viral oncogene homolog, and neuroblastoma RAS viral oncogene homolog (NRAS) belong to the most extensively studied oncogenes and are central players in carcinogenesis. Since their discovery approximately 30 y ago, efforts to target their aberrant activation have not led to major breakthroughs. We herein report the discovery of four so far undescribed variants of NRAS that differ in their expression patterns and, strikingly, in their downstream effects. Our results suggest that NRAS should be studied in the context of its variants. In addition, this discovery may open opportunities to develop more efficient anticancer therapies.

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Ras Family Signaling: Therapeutic Targeting

Cited by 188 publications

References 56 publications

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

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

Serine-phosphorylated STAT1 is a prosurvival factor in Wilms' tumor pathogenesis

NRAS isoforms differentially affect downstream pathways, cell growth, and cell transformation

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