Nitrilase 1 modulates lung tumor progression <i>in vitro</i> and <i>in vivo</i>

Wang, Yong Antican; Sun, Yunguang; Blanc, Justin M Le; Solomides, Charalambos; Lü, Bo

doi:10.18632/oncotarget.7820

Cited by 5 publications

(3 citation statements)

References 34 publications

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“…Noncontrast whole-body CT imaging of 4-to 6-month-old mice without respiratory or cardiac gating was performed using the MicroCAT II small-animal CT scanner (Siemens ImTek Inc.) at 80 kVp and 500 mA (25). The DICOM data were imported to the MIM6.5 (MIM Software Inc.) for tumor contouring and 3D reconstruction with different colors using the combination of manual segmentation and semiautomated contouring methods (26). These analyses were consistent between two independent operators and performed in a blinded manner.…”

Section: Characterization Of Mouse Lung Cancermentioning

confidence: 99%

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

Wang

Sun

Palmer

et al. 2017

Molecular Cancer Research

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Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whether deficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an-null mouse model was generated in combination with to compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non-small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression.-null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase-3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in a mouse model. Furthermore, overexpression of IGFBP3 induced apoptosis and enhanced cisplatin response and confirmed that the suppression is in part by blocking IGF1 signaling. These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1-targeted therapy. .

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Section: Characterization Of Mouse Lung Cancermentioning

confidence: 99%

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

Wang

Sun

Palmer

et al. 2017

Molecular Cancer Research

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“…However, we do not see any obvious connection between the enzymic functions of Fhit and of Nit1. We must also stress that, although data collected in mammalian cells, mice models, and human samples suggest that Nit1 promotes apoptosis (23) and affects, in a complex fashion, the development and progression of some types of tumors (23,43), it is uncertain whether these roles bear any connection with the enzyme's catalytic function. In fact, mutation of the conserved active site cysteine to an alanine did not alter the ability of Nit1 to promote apoptosis in human cells (23).…”

Section: Nit1 Is Useful To Correct the Unspecific Activity Of Transammentioning

confidence: 99%

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

Peracchi

Veiga‐da‐Cunha

Kuhara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian gene Nit1 (nitrilase-like protein 1) encodes a protein that is highly conserved in eukaryotes and is thought to act as a tumor suppressor. Despite being ∼35% sequence identical to ω-amidase (Nit2), the Nit1 protein does not hydrolyze efficiently α-ketoglutaramate (a known physiological substrate of Nit2), and its actual enzymatic function has so far remained a puzzle. In the present study, we demonstrate that both the mammalian Nit1 and its yeast ortholog are amidases highly active toward deaminated glutathione (dGSH; i.e., a form of glutathione in which the free amino group has been replaced by a carbonyl group). We further show that Nit1-KO mutants of both human and yeast cells accumulate dGSH and the same compound is excreted in large amounts in the urine of Nit1-KO mice. Finally, we show that several mammalian aminotransferases (transaminases), both cytosolic and mitochondrial, can form dGSH via a common (if slow) side-reaction and provide indirect evidence that transaminases are mainly responsible for dGSH formation in cultured mammalian cells. Altogether, these findings delineate a typical instance of metabolite repair, whereby the promiscuous activity of some abundant enzymes of primary metabolism leads to the formation of a useless and potentially harmful compound, which needs a suitable "repair enzyme" to be destroyed or reconverted into a useful metabolite. The need for a dGSH repair reaction does not appear to be limited to eukaryotes: We demonstrate that Nit1 homologs acting as excellent dGSH amidases also occur in Escherichia coli and other glutathione-producing bacteria.metabolite repair | deaminated glutathione | amidase | aminotransferases

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“…The deficiency of NIT1 led to an increase in the incidence of N -nitrosomethylbenzylamine-induced murine gastric cancer 23 . However, a recent study has shown that NIT1 was overexpressed in human lung cancer tissues compared with that in non-malignant lung tissues and accelerated lung tumour progression in vitro and in vivo 31 . This inconsistent result may be due to the heterogeneity of the tumours.…”

Section: Discussionmentioning

confidence: 99%

NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer

Lin

Zhang

et al. 2018

Cell Death Dis

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NIT1 protein has been reported to be a potential tumour suppressor in tumour progression. However, little is known about the specific role of NIT1 in tumour development and progression. In this study, we confirmed the specific effects of NIT1 in the regulation of colorectal carcinoma cell proliferation. Here, we showed that NIT1 was significantly downregulated in colorectal cancer tissues compared with that in adjacent normal tissues. The decreased expression of NIT1 was significantly correlated with poor differentiation and more serosal invasion. Functional experiments showed that NIT1 inhibited CRC cell growth both in vitro and in vivo. NIT1 induced cell cycle arrest and apoptosis. Furthermore, NIT1 recruited Smad2/3 to the TGFβ receptor and activated the TGFβ–Smad2/3 pathway by interacting with SARA and SMAD2/3 in CRC. Further study has shown that SMAD3 directly binds to the promoter regions of NIT1 and enhances the transcription of NIT1. Together, our findings indicate that NIT1 suppresses CRC proliferation through a positive feedback loop between NIT1 and activation of the TGFβ–Smad signalling pathway. This study might provide a new promising strategy for CRC.

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Nitrilase 1 modulates lung tumor progression in vitro and in vivo

Cited by 5 publications

References 34 publications

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione

NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer

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