Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels

Harada, Hiroshi; Inoue, Masahiro; Itasaka, Satoshi; Hirota, Kiichi; Morinibu, Akiyo; Shinomiya, Kazumi; Zeng, Lihua; Ou, Guangfei; Zhu, Yubing; Yoshimura, Masataka; McKenna, W. Gillies; Muschel, Ruth J.; Hiraoka, Masahiro

doi:10.1038/ncomms1786

Cited by 155 publications

(145 citation statements)

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“…4 A HIF-1a specific agent could also be used in combination therapy to overcome resistance to chemotherapy and radiation in cancer patients. 5,6 A number of strategies directed at modulation of HIF-1a function were undertaken previously to identify potential cancer therapeutics. Those strategies were mostly aimed at modulation of HIF-1a expression level by compounds affecting its transcription/ translation, 7 compounds activating PHD proteins which promote HIF-1a degradation in a VHL dependent manner, 8 and compounds affecting HIF-1a/ ARNT/p300/CBP complex formation by binding to p300/CBP.…”

Section: Introductionmentioning

confidence: 99%

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

et al. 2012

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The heterodimer HIF-1a (hypoxia inducible factor)/HIF-b (also known as ARNT-aryl hydrocarbon nuclear translocator) is a key mediator of cellular response to hypoxia. The interaction between these monomer units can be modified by the action of small molecules in the binding interface between their C-terminal heterodimerization (PasB) domains. Taking advantage of the presence of several cysteine residues located in the allosteric cavity of HIF-1a PasB domain, we applied a cysteine-based reactomics ''hotspot identification'' strategy to locate regions of HIF1a PasB domain critical for its interaction with ARNT. COMPOUND 5 was identified using a mass spectrometry-based primary screening strategy and was shown to react specifically with Cys255 of the HIF-1a PasB domain. Biophysical characterization of the interaction between PasB domains of HIF-1a and ARNT revealed that covalent binding of COMPOUND 5 to Cys255 reduced binding affinity between HIF-1a and ARNT PasB domains approximately 10-fold. Detailed NMR structural analysis of HIF-1a-PasB-COMPOUND 5 conjugate showed significant local conformation changes in the HIF-1a associated with key residues involved in the HIF-1a/ARNT PasB domain interaction as revealed by the crystal structure of the HIF-1a/ARNT PasB heterodimer. Our screening strategy could be applied to other targets to identify pockets surrounding reactive cysteines suitable for development of small molecule modulators of protein function.

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Section: Introductionmentioning

confidence: 99%

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

et al. 2012

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“…Hypoxia achieves many of its effects through the activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) (10). HIF-1 is recognized as a key player in the transcriptional response to hypoxia (11)(12)(13).…”

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confidence: 99%

“…HIF-1 is recognized as a key player in the transcriptional response to hypoxia (11)(12)(13). HIF-1 is a heterodimer composed of an a-subunit (HIF-1a) and a b-subunit (HIF-1b), and its activity is mainly dependent on the stability and modification of HIF-1a, the expression of which is highly regulated (10,12). In the case of HIF-1a, its synthesis is regulated via O 2 -independent mechanisms, whereas its degradation is regulated primarily via O 2 -dependent mechanisms (10).…”

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confidence: 99%

¹⁸F-Fluoromisonidazole PET Uptake Is Correlated with Hypoxia-Inducible Factor-1α Expression in Oral Squamous Cell Carcinoma

et al. 2013

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Hypoxia is a common feature of cancer and a prognostic factor for many types of cancer. 18 F-fluoromisonidazole ( 18 F-FMISO) PET can detect tumor hypoxia noninvasively. Hypoxia-inducible factor-1 (HIF-1) is a key player in the transcriptional response to low oxygen tension in many types of cancer. Its activity is mainly dependent on the stability and modification of HIF-1a, which is a composition of HIF-1. However, it is unclear whether 18 F-FMISO PET can identify HIF-1a expression in oral squamous cell carcinoma (OSCC). The present study was performed to elucidate the correlation between 18 F-FMISO PET findings and HIF-1a expression in OSCC. Methods: Twenty-three patients (age range, 42-84 y; 15 men, 8 women) with OSCC were enrolled in this study. The T-stages of cancer were T1 in 1 patient, T2 in 9, T3 in 2, and T4a in 11. The N-stages were N0 in 13 patients, N1 in 5, and N2 in 5. Each patient underwent 18 F-FMISO and 18 F-FDG PET before surgery, and the maximum standardized uptake value (SUV max ) of both PET studies was measured. HIF-1a expression in the operation materials was evaluated by immunohistochemical staining. The SUV max of both PET studies and HIF-1a findings were compared statistically. Results: 18 F-FMISO PET detected uptake in the primary site in 14 of the 23 patients (61%). The median SUV max of 18 F-FMISO and 18 F-FDG PET in the primary site was 1.83 (range, 0.8-2.7) and 16.5 (range, 1.0-32.3), respectively. There was a weak significant correlation between 18 F-FMISO and 18 F-FDG PET SUV max (P 5 0.02, r 5 0.48). HIF-1a expression was clearly detected in 11 of the 23 patients (48%). The 18 F-FMISO PET SUV max was significantly higher in the HIF-1a-positive cases than in the HIF-1a-negative cases (median, 2.1; range, 1.5-2.4, vs. median, 1.6; range, 0.8-2.0, respectively) (P 5 0.002). However, there were no significant correlations between 18 F-FDG PET SUV max and HIF-1a expression (median, 21.8; range, 7.7-29.1 vs. 1.0-32.2) (P 5 0.06). Conclusion: 18 F-FMISO uptake in the primary site of OSCC indicates a hypoxic environment with HIF-1a expression.

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“…Recently, it has been reported that the peri-necrotic tumor cells after radiation therapy acquire hypoxia-inducible factor 1 (HIF-1) activity after surviving radiation, which triggers their translocation towards tumor blood vessels. So, the HIF-1 inhibitors suppress the incidence of post-irradiation tumor recurrence [47].…”

Section: Perspectivementioning

confidence: 99%

DNA Repair Molecules and Cancer Therapeutical Responses

Kobayashi¹,

Matsuda²

2013

Oncogene and Cancer - From Bench to Clinic

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Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels

Cited by 155 publications

References 50 publications

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

¹⁸F-Fluoromisonidazole PET Uptake Is Correlated with Hypoxia-Inducible Factor-1α Expression in Oral Squamous Cell Carcinoma

DNA Repair Molecules and Cancer Therapeutical Responses

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Cancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels

Cited by 155 publications

References 50 publications

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

Identification of Cys255 in HIF‐1α as a novel site for development of covalent inhibitors of HIF‐1α/ARNT PasB domain protein–protein interaction

18F-Fluoromisonidazole PET Uptake Is Correlated with Hypoxia-Inducible Factor-1α Expression in Oral Squamous Cell Carcinoma

DNA Repair Molecules and Cancer Therapeutical Responses

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¹⁸F-Fluoromisonidazole PET Uptake Is Correlated with Hypoxia-Inducible Factor-1α Expression in Oral Squamous Cell Carcinoma