Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Glück, Astrid A.; Aebersold, Daniel M.; Zimmer, Yitzhak; Medová, Michaela

doi:10.1016/j.biocel.2015.02.018

Cited by 23 publications

(18 citation statements)

References 186 publications

(288 reference statements)

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“…Hypoxia modulates the microenvironment and the extracellular matrix to facilitate tumor growth, whereas alterations in gene expression profiles and signaling events in cancer cells per se dictate their malignant phenotypes, including chemotherapy resistance [21, 22]. Cancer cells may acquire resistance to chemotherapy through the hypoxia-induced expression of drug-pumping proteins, such as multidrug resistance 1 (MDR1)/p-glycoprotein (P-gp)/ABCB1, a known transcriptional target of HIF-1 [23].…”

Section: Discussionmentioning

confidence: 99%

“…Cancer cells may acquire resistance to chemotherapy through the hypoxia-induced expression of drug-pumping proteins, such as multidrug resistance 1 (MDR1)/p-glycoprotein (P-gp)/ABCB1, a known transcriptional target of HIF-1 [23]. Alternatively, hypoxia indirectly induces drug resistance by promoting malignant behaviors such as cell survival, proliferation, and migration, which occurs through the activation of oncogenic signaling or the impairment of the cell death or differentiation machinery [4, 22]. Consistent with these paradigms, we established here that UCP2 is downregulated in response to decreased environmental oxygen supply in NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

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Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer

Wang

Yang

et al. 2016

Oncotarget

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Hypoxic microenvironment is critically involved in the response of non-small cell lung cancer (NSCLC) to chemotherapy, the mechanisms of which remain largely unknown. Here, we found that NSCLC patients exhibited increased chemotherapeutic resistance when complicated by chronic obstructive pulmonary disease (COPD), a critical cause of chronic hypoxemia. The downregulation of uncoupling protein 2 (UCP2), which is attributed to hypoxia-inducible factor 1 (HIF-1)-mediated suppression of the transcriptional factor peroxisome proliferator-activated receptor γ (PPARγ), was involved in NSCLC chemoresistance, and predicted a poor survival rate of patients receiving routine chemotherapy. UCP2 suppression induced reactive oxygen species production and upregulation of the ABC transporter protein ABCG2, which leads to chemoresistance by promoting drug efflux. UCP2 downregulation also altered metabolic rates as shown by elevated glucose uptake and reduced oxygen consumption. These data suggest that UCP2 is a key mediator of hypoxia-triggered chemoresistance of NSCLCs, which can be potentially targeted in clinical treatment of chemo-refractory NSCLCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer

Wang

Yang

et al. 2016

Oncotarget

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“…Multiple mechanisms for oxygen sensing have been developed and conserved in both prokaryotic and eukaryotic organisms (32)(33)(34). In particular, HIF-1 acts as a master regulator of the adaptive cell response to limited oxygen availability mainly by activating the transcription of genes that regulate physiological processes as glycolysis, survival, and angiogenesis (34)(35)(36)(37). HIF-1 is a heterodimer of two helix-loop-helix-PAS proteins, namely HIF-1α and HIF-1β or ARNT (38).…”

Section: Gpcr Involvement In Hypoxia-mediated Signalingmentioning

confidence: 99%

“…In particular, HIF-1α regulates the expression of several pro-angiogenic factors involved in tumor angiogenesis progression (34,35). Many signaling cascades are engaged by hypoxia toward HIF-1α activation such as receptor tyrosine kinases (RTKs) and GPCRs (30,31,36). Here, we discuss the involvement of certain GPCRs, including GPER, in hypoxia-mediated signaling toward cancer development and cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Lappano

Rigiracciolo

Marco

et al. 2016

AAPS J

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Abstract. G protein-coupled receptors (GPCRs) are cell surface proteins mainly involved in signal transmission; however, they play a role also in several pathophysiological conditions. Chemically heterogeneous molecules like peptides, hormones, lipids, and neurotransmitters activate second messengers and induce several biological responses by binding to these seven transmembrane receptors, which are coupled to heterotrimeric G proteins. Recently, additional molecular mechanisms have been involved in GPCR-mediated signaling, leading to an intricate network of transduction pathways. In this regard, it should be mentioned that diverse GPCR family members contribute to the adaptive cell responses to low oxygen tension, which is a distinguishing feature of several illnesses like neoplastic and cardiovascular diseases. For instance, the G protein estrogen receptor, namely G protein estrogen receptor (GPER)/GPR30, has been shown to contribute to relevant biological effects induced by hypoxia via the hypoxia-inducible factor (HIF)-1α in diverse cell contexts, including cancer. Likewise, GPER has been found to modulate the biological outcome of hypoxic/ischemic stress in both cardiovascular and central nervous systems. Here, we describe the role exerted by GPCR-mediated signaling in low oxygen conditions, discussing, in particular, the involvement of GPER by a hypoxic microenvironment.

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“…Despite the role of MET signaling in tumor angiogenesis [24, 25, 45] and the possible therapeutic benefit of targeting MET aberrant expression in liver tumors, the impact of MET inhibition on liver cancer-associated angiogenesis has not been yet adequately reported. Consequently, in the current study we aimed to investigate the impact of aberrant MET activity targeting on pro-angiogenic activities in MET-driven tumor cells and in a liver xenograft model.…”

Section: Discussionmentioning

confidence: 99%

Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

et al. 2015

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Deregulated expression of the MET receptor tyrosine kinase has been reported in up to 50% of patients with hepatocellular carcinoma, the most abundant form of liver cancers, and is associated with decreased survival. Consequently, MET is considered as a molecular target in this malignancy, whose progression is highly dependent on extensive angiogenesis. Here we studied the impact of MET small molecule inhibitors on angiogenesis-associated parameters and growth of xenograft liver models consisting of cells expressing MET-mutated variants M1268T and Y1248H, which exhibit constitutive kinase activity. We demonstrate that MET mutations expression is associated with significantly increased production of vascular endothelial growth factor, which is blocked by MET targeting only in cells expressing the M1268T inhibitor-sensitive but not in the Y1248H inhibitor-resistant variant. Decrease in vascular endothelial growth factor production is also associated with reduction of tyrosine phopshorylation of the vascular endothelial growth factor receptor 2 expressed on primary liver sinusoidal endothelial cells and with inhibition of vessel formation. Furthermore, MET inhibition demonstrated an efficient anti-tumor activity and considerable reduction in microvessel density only against the M1268T-derived intrahepatic tumors. Collectively, our data support the role of targeting METassociated angiogenesis as a major biological determinant for liver tumor growth control.

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Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Cited by 23 publications

References 186 publications

Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer

Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer

Recent Advances on the Role of G Protein-Coupled Receptors in Hypoxia-Mediated Signaling

Impact of MET targeting on tumor-associated angiogenesis and growth of MET mutations-driven models of liver cancer

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