Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

Toulany, Mahmoud; Baumann, Michaël; Rodemann, H. Peter

doi:10.1158/1541-7786.mcr-06-0297

Cited by 95 publications

(86 citation statements)

References 55 publications

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“…10). Although challenging the signalling dogma holding that the GTPase-dependent stimulation of PI3Ka is mostly mediated by direct physical interactions with oncogenic Ras proteins 33 , these results are consistent with previous data indicating that the PI3Ka/Akt axis can be activated in Ras-independent manners in some Ras-transformed cells 16,24,[34][35][36][37] . Interestingly, the influence of R-Ras2 on the PI3K/Akt pathway is highly dependent on the experimental conditions used.…”

Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismssupporting

confidence: 91%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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R-Ras2 is a transforming GTPase that shares downstream effectors with Ras subfamily proteins. However, little information exists about the function of this protein in tumorigenesis and its signalling overlap with classical Ras GTPases. Here we show, by combining loss-and gain-of-function studies in breast cancer cells, mammary epithelial cells and mouse models, that endogenous R-Ras2 has a role in both primary breast tumorigenesis and the late metastatic steps of cancer cells in the lung parenchyma. R-Ras2 drives tumorigenesis in a phosphatidylinostiol-3 kinase (PI3K)-dependent and signalling autonomous manner. By contrast, its prometastatic role requires other priming oncogenic signals and the engagement of several downstream elements. R-Ras2 function is required even in cancer cells exhibiting constitutive activation of classical Ras proteins, indicating that these GTPases are not functionally redundant. Our results also suggest that application of long-term R-Ras2 therapies will result in the development of compensatory mechanisms in breast tumours.

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Section: R-ras2 Deficient Tumours Develop Compensatory Mechanismssupporting

confidence: 91%

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

et al. 2014

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“…Recent reports indicate that PI3K-mediated activation of AKT in mutant K-RAS-expressing human cancer cells in response to EGFR ligand binding or radiation is independent of a direct K-RAS function but dependent on increased production of EGFR ligands mediated by upregulation of K-RAS/ERK signaling (24). This observation provided new insight into the importance of K-RAS mutation in the context of PI3K/AKT-mediated radioresistance in EGFR-activated tumors.…”

Section: Discussionmentioning

confidence: 93%

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

Choi

Ryu

Kim

et al. 2010

Molecular Cancer Research

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Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non-small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G 2 arrest following irradiation and induced γH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation.

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“…3A). Furthermore, inhibition of ERK1/2 has been reported to impair the production of EGFR ligands (39). As shown in Fig.…”

Section: Erb1 Activates the Intrinsic Apoptotic Pathway In Nsclc Cellmentioning

confidence: 89%

ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

Nikolos

Thomas

Rajapaksa

et al. 2014

Molecular Cancer Research

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. In addition to the aberrant growth factor signaling, dysregulation of other pathways, such as those mediated by estrogens and their receptors, has been linked to NSCLC initiation and progression. Although the expression of wild-type estrogen receptor b (ERb1) has been associated with prolonged disease-free survival in patients with NSCLC, the molecular mechanism that accounts for this correlation is unknown. Here, upregulation of ERb1 reduced proliferation and enhanced apoptosis in the context of mutant RAS. ERb1 was found to induce apoptosis by stimulating the intrinsic apoptotic pathway that involves BIM, a Bcl-2 proapoptotic family member that is regulated by the extracellular signal-regulated kinase (ERK). Downregulation of EGFR and inactivation of RAS and the downstream components ERK1/2 were found to be involved in the ERb1-induced apoptosis. Manipulation of EGFR and RAS expression and activity in ERb1-expressing cells revealed the central role of oncogenic RAS inhibition in the ERb1-mediated proapoptotic phenotype and EGFR regulation. These results demonstrate that ERb1 decreases the survival of NSCLC cells by regulating oncogenic RAS signaling.

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Stimulated PI3K-AKT Signaling Mediated through Ligand or Radiation-Induced EGFR Depends Indirectly, but not Directly, on Constitutive K-Ras Activity

Abstract: Previous results showed an inducible radiation sensitivity selectively observable for K-RAS -mutated cell lines as a function of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor blockade of phosphatidylinositol 3-kinase (PI3K)-AKT signaling.

Cited by 95 publications

References 55 publications

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Contribution of the R-Ras2 GTP-binding protein to primary breast tumorigenesis and late-stage metastatic disease

Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response

ERβ Regulates NSCLC Phenotypes by Controlling Oncogenic RAS Signaling

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