Expression Pattern of Carbonic Anhydrase IX in Medullary Thyroid Carcinoma Supports a Role for RET-Mediated Activation of the HIF Pathway

Takáčová, Martina; Bullova, Petra; Simko, Veronika; Škvarková, Lucia; Poturnajova, Martina; Feketeova, Lucia; Babál, Pavel; Kivelä, Antti; Kuopio, Teijo; Kopáček, Juraj; Pastorek, Jaromı́r; Parkkila, Seppo; Pastoreková, Silvia

doi:10.1016/j.ajpath.2014.01.002

Cited by 32 publications

(24 citation statements)

References 55 publications

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“…HIFs bind to hypoxia response elements in the promoter regions of targeted genes and are rapidly degraded upon exposure to oxygen, such as in the normoxic regions inside solid tumors [11,12]. Hypoxic microenvironments are frequently observed in many human cancers including MTC; HIF-1α and HIF-2α are found to be overexpressed in MTC and contribute to tumor progression and the resistance to chemotherapy regiments [13,14]. VEGF [11,12] and HGF [15,16] are the downstream factors of HIF-1.…”

Section: Introductionmentioning

confidence: 99%

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

et al. 2015

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Cabozantinib is a multi-targeted tyrosine kinase inhibitor targeting vascular endothelial growth factor (VEGF) receptor (VEGFR)-2, MET (c-Met, also called hepatocyte growth factor (HGF) receptor), and other receptor tyrosine kinases. Cabozantinib has recently been approved for treating advanced medullary thyroid carcinoma (MTC), but its long-term benefit remains uncertain and dose-dependent adverse events are very common. The present study has demonstrated that 2-methoxyestradiol (2ME2), an inhibitor of hypoxia-inducible factors (HIFs) and a promising anticancer agent under investigation in clinical trials, strengthens anticancer activities of cabozantinib against MTC cells in vitro and in vivo. The activated hypoxia-inducible pathways, which are mainly regulated by HIF-1, contribute to the resistance of hypoxic MTC cells to cabozantinib. Cabozantinib upregulated HIF-1α expression at translational levels and increased the expression of the downstream factors including VEGF, lactate dehydrogenase A (LDHA), HGF, and MET. 2ME2 corrected the activated pathways by cabozantinib through downregulating HIF-1α expression and inhibiting its nuclear translocation in hypoxic MTC cells. Administration of 2ME2 enhanced the efficacy of cabozantinib in suppressing the growth of MTC cell line xenografts and patient-derived xenografts established in mice. Given that 2ME2 targets insensitive hypoxic cancer cells to cabozantinib and can inhibit the activated pathways by cabozantinib, the present results warrant further investigation of 2ME2, particularly in combination with cabozantinib, for the treatment of MTC.

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Section: Introductionmentioning

confidence: 99%

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

et al. 2015

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“…Functional pathway analysis revealed the enrichment of several pathways that were previously implicated in breast cancer. These include ErbB signaling pathway [48][49][50], Insulin signaling pathway [48], cell cycle pathways [51], p53 signaling pathway [29,52,53], and TGFβ signaling pathway [54-56]…”

Section: Discussionmentioning

confidence: 99%

A probabilistic approach for automated discovery of perturbed genes using expression data from microarray or RNA-Seq

Sundaramurthy

Eghbalnia

2015

Computers in Biology and Medicine

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“…Overexpression of RET, which mimics ligand-independent activation often occurring in advanced medullary thyroid carcinomas, increases CAIX promoter activity induced by HIF-1α in a cellular model [167]. It is suggested that both PI3K and MAPK pathways can mediate this phenomenon [167].…”

Section: Pdgfr Fgfr and Retmentioning

confidence: 99%

“…It is suggested that both PI3K and MAPK pathways can mediate this phenomenon [167]. The crosstalk between RET and HIF-1α has been described also in neuroblastoma cells, where activation of RET induced by its ligand GDNF increases HIF-1α protein levels [130].…”

Section: Pdgfr Fgfr and Retmentioning

confidence: 99%

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

Glück

Aebersold

Zimmer

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Expression Pattern of Carbonic Anhydrase IX in Medullary Thyroid Carcinoma Supports a Role for RET-Mediated Activation of the HIF Pathway

Cited by 32 publications

References 55 publications

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

2ME2 inhibits the activated hypoxia-inducible pathways by cabozantinib and enhances its efficacy against medullary thyroid carcinoma

A probabilistic approach for automated discovery of perturbed genes using expression data from microarray or RNA-Seq

Interplay between receptor tyrosine kinases and hypoxia signaling in cancer

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