Epidermal Growth Factor and Hypoxia-induced Expression of CXC Chemokine Receptor 4 on Non-small Cell Lung Cancer Cells Is Regulated by the Phosphatidylinositol 3-Kinase/PTEN/AKT/Mammalian Target of Rapamycin Signaling Pathway and Activation of Hypoxia Inducible Factor-1α

Phillips, Roderick J.; Mestas, Javier; Gharaee−Kermani, Mehrnaz; Burdick, Marie D.; Sica, Antonio; Belperio, John A.; Keane, Michael P.; Strieter, Robert M.

doi:10.1074/jbc.m500963200

Cited by 303 publications

(278 citation statements)

References 41 publications

(84 reference statements)

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“…Although EGFR was suggested to be one of upstream regulators of PDK-1/AKT and Stat3 pathways (Engelman et al, 2005;Ivanov and Hei, 2005;Phillips et al, 2005), the role of EGFR activation plays in relation to PDK-1/AKT/mTOR/p70S6K/S6 cascade in breast cancers has not been firmly established. In this study, we have shown that moderate to high levels of EGFR phosphorylation (Y1086) were observed in 67 out of 89 (75.3%) primary breast tumours and was associated with invasive breast tumours (Po0.05) (Table 1).…”

Section: Phosphorylated Egfr(y1068) Was Exclusively In the Nucleus Ofmentioning

confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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Activation of kinases signalling pathways contributes to various malignant phenotypes in human cancers, including breast tumour. To examine the possible activation of these signalling molecules, we examined the phosphorylation status in 12 protein kinases and transcription factors in normal primary human mammary epithelial cells, telomerase-immortalised human breast epithelial cell line, and two breast cancer lines, MDA-MB-468 and MCF-7, using Kinexus phosphorylated protein screening assays. The phosphorylation of FAK, mTOR, p70S6K, and PDK-1 were elevated in both breast cancer cell lines, whereas the phosphorylation of AKT, EGFR, ErbB2/ Her2, PDGFR, Shc, and Stat3 were elevated in only one breast cancer line compared to normal primary mammary epithelial cells and telomerase-immortalised breast epithelial cells. The same findings were confirmed by Western blotting and by kinase assays. We further substantiated the phosphorylation status of these molecules in tissue microarray slides containing 89 invasive breast cancer tissues as well as six normal mammary tissues with immunohistochemistry staining using phospho-specific antibodies. Consistent findings were obtained as greater than 70% of invasive breast carcinomas expressed moderate to high levels of phosphorylated PDK-1, AKT, p70S6K, and EGFR. In sharp contrast, phosphorylation of the same proteins was nearly undetectable or was at low levels in normal mammary tissues under the same assay. Elevated phosphorylation of PDK-1, AKT, mTOR, p70S6K, S6, EGFR, and Stat3 were highly associated with invasive breast tumours (Po0.05). Taken together, our results suggest that activation of these kinase pathways by phosphorylation may in part account for molecular pathogenesis of human breast carcinoma. Particularly, moderate to high level of PDK-1 phosphorylation was found in 86% of high-grade metastasised breast tumours. This is the first report demonstrating phosphorylation of PDK-1 is frequently elevated in breast cancer with concomitantly increased phosphorylation of downstream kinases, including AKT, mTOR, p70S6K, S6, and Stat3. This finding thus suggested PDK-1 may promote oncogenesis in part through the activation of AKT and p70S6K and rationalised that PDK-1 as well as downstream components of PDK-1 signalling pathway may be promising therapeutic targets to treat breast cancer. Breast cancer remains to be a major cause of death in women worldwide, despite improvements in cancer prevention, early detection, treatment, and understanding the molecular pathogenesis. It hence demands an urgent need to unveil the exact mechanism of oncogenesis and tumour progression, which may prelude the development of new strategies for treatment. Breast carcinoma emerges through multistep processes progressing from hyperplasia to premalignant change, in situ carcinoma, invasion, and distal metastasis, in concomitant with gain of oncogenic activities and loss of tumour suppressor gene functions.Protein kinases have been implicated in playing crucial roles in regulating cell growth, met...

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Section: Phosphorylated Egfr(y1068) Was Exclusively In the Nucleus Ofmentioning

confidence: 99%

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

et al. 2005

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“…[6][7][8][9] Hypoxia association with treatment failure is exhibited as resistance to radiotherapy and chemotherapy and the presence of quiescent hypoxic cells resistant to anti-proliferative therapy. 5 The contribution of hypoxia to a more aggressive, invasive, and metastatic phenotype involves multiple mechanisms, including: promotion of genetic 10 and epigenetic changes; 11 inhibition of apoptosis; 12 a shift to glycolytic metabolism; 13 up-regulation of survival factors; 14 production of enzymes mediating invasiveness; 15 stimulation of angiogenic signals; 15 induction of epithelial to mesenchymal transition (EMT); 16 and preferential location of cancer stem cells to hypoxic subregions. 17 TH-302 (1-Methyl-2-nitro-1H-imidazol-5-yl)methyl N,N 0 -bis(2-bromoethyl)phosphorodiamidate) is a hypoxia-activated prodrug composed of 2-nitroimidazole linked to a brominated analog of isophosphoramide mustard (Br-IPM).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Sun

Liu

Ahluwalia

et al. 2015

Cancer Biology & Therapy

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“…Hypoxia-inducible factor 1 is degraded through ubiquitylation involving the von Hippel -Lindau tumour-suppressor protein, whose loss of function, detected in renal cancer and neuroendocrine tumours, impairs HIF-1a degradation and favours the stimulation of mTOR signalling (Melillo, 2007). Finally, it has been reported that HER2 activation in normoxic cells increases HIF-1a via PI3K, Akt and mTOR (Laughner et al, 2001), and that EGF induces HIF-1a, which can be prevented by using mTOR inhibitors under both normoxic and hypoxic conditions (Phillips et al, 2005). Taken together, these studies demonstrate that mTOR is a positive regulator of HIF-1a translation and an inducer of HIF-1/VEGFdependent angiogenesis.…”

mentioning

confidence: 99%

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

et al. 2008

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Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo . We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

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Epidermal Growth Factor and Hypoxia-induced Expression of CXC Chemokine Receptor 4 on Non-small Cell Lung Cancer Cells Is Regulated by the Phosphatidylinositol 3-Kinase/PTEN/AKT/Mammalian Target of Rapamycin Signaling Pathway and Activation of Hypoxia Inducible Factor-1α

Cited by 303 publications

References 41 publications

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer

Efficacy and safety of the hypoxia-activated prodrug TH-302 in combination with gemcitabine and nab-paclitaxel in human tumor xenograft models of pancreatic cancer

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

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