Etk/Bmx Transactivates Vascular Endothelial Growth Factor 2 and Recruits Phosphatidylinositol 3-Kinase to Mediate the Tumor Necrosis Factor-induced Angiogenic Pathway

Zhang, Rong; Xu, Yu; Ekman, Niklas; Wu, Zhenhua; Wu, Jiong; Alitalo, Kari; Wang, Min

doi:10.1074/jbc.m310678200

Cited by 140 publications

(145 citation statements)

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“…We demonstrate that inhibition of PI3K pathway signaling can increase the sensitivity of SCLC cells (H1048 and H526) to a BCL-2/BCLx L targeting BH3 mimetic via increased apoptosis. Our data in SCLC cell lines in vitro were recapitulated in vivo in the H1048 xenograft and a newly developed CDX from a chemorefractory patient (43). These data provide additional weight to an increasing body of evidence to suggest SCLC clinical trials of combined PI3K/mTOR pathway inhibitors and BH3 mimetics are warranted.…”

Section: Discussionmentioning

confidence: 64%

“…S4B) reduced activation of pathways downstream of BMX, including AKT and mTOR, consistent with on target effects. The mechanism by which BMX regulates AKT/mTOR signaling in SCLC is not yet clear, but precedents that link BMX to AKT/mTOR signaling exist in other cell types (43,44). Addressing the mechanistic role for BMX in regulating this signaling axis may aid in development of predictive biomarkers as well as unveil a new therapeutic opportunity for the treatment of SCLC.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo. These data add to a body of evidence that this combination should move toward the clinic.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Potter

Galvin

Brown

et al. 2016

Molecular Cancer Therapeutics

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“…In a study of UC and CD patients TNF-␣ receptor levels were found to be elevated during both active and remission phases of disease, suggesting the possibility that TNF-␣ receptors may mediate angiogenic activity in IBD (31,145). Importantly, TNF-␣ receptor activation can facilitate transactivation of VEGFR2 through the Etk pathway, resulting in mimicked VEGF-A angiogenic simulation (110,168). Additionally, CD40, a member of the TNF receptor gene family, and CD40 ligand (CD40L or CD154) interactions are multifunctional effectors of the immune response that cause upregulation of adhesion molecules on endothelial cells and increased expression of cytokines and chemokines by immune cells.…”

Section: Angiogenic Mediators In Ibd and Experimental Colitismentioning

confidence: 99%

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Chidlow

Shukla²,

Grisham³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

144

114

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Chidlow JH Jr, Shukla D, Grisham MB, Kevil CG. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am J Physiol Gastrointest Liver Physiol 293: G5-G18, 2007. First published April 26, 2007; doi:10.1152/ajpgi.00107.2007.-Angiogenesis is now understood to play a major role in the pathology of chronic inflammatory diseases and is indicated to exacerbate disease pathology. Recent evidence shows that angiogenesis is crucial during inflammatory bowel disease (IBD) and in experimental models of colitis. Examination of the relationship between angiogenesis and inflammation in experimental colitis shows that initiating factors for these responses simultaneously increase as disease progresses and correlate in magnitude. Recent studies show that inhibition of the inflammatory response attenuates angiogenesis to a similar degree and, importantly, that inhibition of angiogenesis does the same to inflammation. Recent data provide evidence that differential regulation of the angiogenic mediators involved in IBD-associated chronic inflammation is the root of this pathological angiogenesis. Many factors are involved in this phenomenon, including growth factors/cytokines, chemokines, adhesion molecules, integrins, matrix-associated molecules, and signaling targets. These factors are produced by various vascular, inflammatory, and immune cell types that are involved in IBD pathology. Moreover, recent studies provide evidence that antiangiogenic therapy is a novel and effective approach for IBD treatment. Here we review the role of pathological angiogenesis during IBD and experimental colitis and discuss the therapeutic avenues this recent knowledge has revealed. inflammation; T cells; growth factors; adhesion molecules; antiangiogenesis ANGIOGENESIS PLAYS AN IMPORTANT role in many chronic inflammatory diseases including but not limited to diabetic retinopathy, atherosclerosis, rheumatoid arthritis, hypercholesterolemia, and psoriasis. It has been suggested that the angiogenic components of these diseases contribute to and exacerbate disease conditions (26, 31). Recent findings, both clinical and experimental, indicate that angiogenesis also plays a crucial role in the inflammatory bowel diseases (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC) (31,37,58,131,155). Development of new vasculature during chronic inflammation may play a negative "pathological" role by contributing to increased inflammatory responses due to dysfunctional new vessel architecture and increases in the recruitment of inflammatory cell types. Importantly, recent data have shown that angiogenic inhibition during chronic inflammatory diseases attenuates further inflammation and disease pathology (31, 37, 51). As such, expanding our knowledge of how pathological angiogenesis occurs during IBD will further our ability to treat patients with these diseases. IBD PathogenesisCD and UC are idiopathic inflammatory disorders of the intestine and/or colon in which patients suffer from rectal bleeding, severe...

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“…25 On the other hand, TNFR2 can specifically activate Akt through interactions between ETK tyrosine kinase and VEGFR2 in endothelial cells. 26 A more complete elucidation of these receptormediated pathways in the myocardium may provide novel insights into the role of TNF-␣ and/or TNF receptors as targets for therapeutic interventions in patients with heart failure. …”

Section: Myocardial Protein Levels Of Tnf-␣ and Receptorsmentioning

confidence: 99%

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

Higuchi¹,

et al. 2004

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Background-Tumor necrosis factor (TNF)-␣ plays a pathophysiological role in heart failure. Although both TNF receptor 1 (TNFR1) and 2 (TNFR2) are present in the heart, comparatively little is known about the role of TNFR2. Methods and Results-We bred TNFR1-knockout (KO) or TNFR2KO mice to transgenic (TG) mice with cardiac-specific overexpression of TNF-␣ and analyzed resultant progeny. Six groups of male and female mice were studied: wild type (WT) with wild receptors (WT/W), TG with wild receptors (TG/W), TG with heterozygous receptor KO (TG/R1 ϩ/Ϫ or TG/R2 ϩ/Ϫ ), and TG with homozygous receptor KO (TG/R1 Ϫ/Ϫ or TG/R2 Ϫ/Ϫ ). Both male and female TG mice displayed cardiac hypertrophy, dilation, and reduced cardiac function. Male TG mice were more severely affected than genotypically matched females and died of heart failure at a younger age. Survival, cardiac function, and remodeling of TG/R1 ϩ/Ϫ and TG/R1 Ϫ/Ϫ mice were improved relative to TG/W mice in both males and females. However, the survival of female TG/R2 ϩ/Ϫ and TG/R2 Ϫ/Ϫ mice was worse than that of TG/W mice, with increased left ventricular dimension and left ventricular weight/body weight ratios. The cardiac TNF-␣ protein level was upregulated in TG/R1

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Etk/Bmx Transactivates Vascular Endothelial Growth Factor 2 and Recruits Phosphatidylinositol 3-Kinase to Mediate the Tumor Necrosis Factor-induced Angiogenic Pathway

Cited by 140 publications

References 50 publications

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Tumor Necrosis Factor Receptors 1 and 2 Differentially Regulate Survival, Cardiac Dysfunction, and Remodeling in Transgenic Mice With Tumor Necrosis Factor-α–Induced Cardiomyopathy

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