Dataset Information

NOV-002, A Glutathione Disulfide Mimetic, Suppresses Tumor Cell Invasion and Metastasis.

ABSTRACT: Metastasis is the major cause of death in cancer. Most therapies currently in the clinic aim to eradicate primary tumor, but do not have ideal effects on metastasis. The lack of effective therapy in metastasis prevention and treatment results in high mortality rate in cancer patients with advanced diseases. Here we report the oxidized glutathione small molecule compound NOV-002 reduces cancer cell invasion in vitro and metastasis in an animal model in combination with chemotherapy drug gemcitabine. NOV-002 regulates cell signaling pathways by suppressing ErbB2 and PI3K phosphorylation and subsequent inhibition of Akt and RhoA activation. Our results suggest that NOV-002 affects cell signaling pathways that are critical for invasion and metastasis and can potentially be effective in metastasis treatment in combination of other chemotherapies.

SUBMITTER: Gumireddy K

PROVIDER: S-EPMC3872994 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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NOV-002, A Glutathione Disulfide Mimetic, Suppresses Tumor Cell Invasion and Metastasis.

Gumireddy Kiranmai K Li Anping A Cao Lili L Yan Jinchun J Liu Lin L Xu Xiaowei X Pazoles Christopher C Huang Qihong Q

Journal of carcinogenesis & mutagenesis 20130401

Metastasis is the major cause of death in cancer. Most therapies currently in the clinic aim to eradicate primary tumor, but do not have ideal effects on metastasis. The lack of effective therapy in metastasis prevention and treatment results in high mortality rate in cancer patients with advanced diseases. Here we report the oxidized glutathione small molecule compound NOV-002 reduces cancer cell invasion <i>in vitro</i> and metastasis in an animal model in combination with chemotherapy drug ge ...[more]

PMID: 24377058

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Project description:BackgroundSmac mimetics are a type of drug that can induce apoptosis by antagonizing IAP family members in cancer treatment. However, a recent study showed that Smac mimetics can trigger cell invasion and migration in cancer cells by activating the NF-κB pathway.MethodsWe assessed lung cancer cell elongation, invasion and migration under treatment with the Smac mimetic LCL161. Functional analyses (in vitro and in vivo) were performed to detect the contribution of NIK and OTUD7B to LCL161-induced cell invasion and migration. The role of OTUD7B in regulation of the TRAF3/NIK/NF-κB pathway under LCL161 treatment was analysed by immunoblotting, immunoprecipitation, luciferase and ubiquitin assays, shRNA silencing and plasmid overexpression. Expression levels of OTUD7B, NIK and TRAF3 in tissue samples from lung cancer patients were examined by immunohistochemistry.ResultsWe found that LCL161 stimulates lung cancer cell elongation, invasion and migration at non-toxic concentrations. Mechanistically, LCL161 results in NIK accumulation and activates the non-canonical rather than the canonical NF-κB pathway to enhance the transcription of target genes, such as IL-2 and MMP-9. Importantly, knockdown of NIK dramatically suppresses LCL161-induced cell invasion and migration by reducing the proteolytic processing of p100 to p52 and target gene transcription. Interestingly, we discovered that OTUD7B increases TRAF3 and decreases NIK to inhibit the non-canonical NF-κB pathway and that overexpression of OTUD7B suppresses LCL161-induced cell invasion and migration. Notably, OTUD7B directly binds to TRAF3 rather than to NIK and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing NIK accumulation and NF-κB pathway activation. Furthermore, the OTU domain of OTUD7B is required for the inhibition of LCL161-induced cell invasion and migration, as demonstrated by transfection of the C194S/H358R(CH) mutant OTUD7B. Finally, we investigated whether OTUD7B inhibits LCL161-induced lung cancer cell intrapulmonary metastasis in vivo, and our analysis of clinical samples was consistent with the above findings.ConclusionsOur study highlights the importance of OTUD7B in the suppression of LCL161-induced lung cancer cell invasion and migration, and the results are meaningful for selecting lung cancer patients suitable for LCL161 treatment.

Dataset Information

NOV-002, A Glutathione Disulfide Mimetic, Suppresses Tumor Cell Invasion and Metastasis.

Publications

NOV-002, A Glutathione Disulfide Mimetic, Suppresses Tumor Cell Invasion and Metastasis.

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