Nitric oxide increases the migratory activity of non-small cell lung cancer cells via AKT-mediated integrin αv and β1 upregulation

Saisongkorh, Vhudhipong; Maiuthed, Arnatchai; Chanvorachote, Pithi

doi:10.1007/s13402-016-0287-3

Cited by 16 publications

(22 citation statements)

References 40 publications

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“…An aberrantly high expression of NO was also shown to be correlated with poor prognosis of several cancers. These clinical data are consistent with previous experimental data by our groups and others showing the stimulating effect of NO on cancer cell aggressiveness (22)(23)(24)(25)(26).…”

Section: Discussionsupporting

confidence: 92%

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Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Maiuthed

Bhummaphan

Luanpitpong

et al. 2018

Journal of Biological Chemistry

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Cancer stem cells (CSCs) are unique populations of cells that can self-renew and generate different cancer cell lineages. Although CSCs are believed to be a promising target for novel therapies, the specific mechanisms by which these putative therapeutics could intervene are less clear. Nitric oxide (NO) is a biological mediator frequently up-regulated in tumors and has been linked to cancer aggressiveness. Here, we search for targets of NO that could explain its activity. We find that it directly affects the stability and function of octamer-binding transcription factor 4 (Oct4), known to drive the stemness of lung cancer cells. We demonstrated that NO promotes the CSC-regulatory activity of Oct4 through a mechanism that involves complex formation between Oct4 and the scaffolding protein caveolin-1 (Cav-1). In the absence of NO, Oct4 forms a molecular complex with Cav-1, which promotes the ubiquitin-mediated proteasomal degradation of Oct4. NO promotes Akt-dependent phosphorylation of Cav-1 at tyrosine 14, disrupting the Cav-1:Oct4 complex. Site-directed mutagenesis and computational modeling studies revealed that the hydroxyl moiety at tyrosine 14 of Cav-1 is crucial for its interaction with Oct4. Both removal of the hydroxyl via mutation to phenylalanine and phosphorylation lead to an increase in binding free energy (Δ) between Oct4 and Cav-1, destabilizing the complex. Together, these results unveiled a novel mechanism of CSC regulation through NO-mediated stabilization of Oct4, a key stem cell transcription factor, and point to new opportunities to design CSC-related therapeutics.

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Section: Discussionsupporting

confidence: 92%

“…In lung cancer, NO and its producing enzymes, nitric-oxide synthases (NOSs), are highly up-regulated (19,21). NO has also been shown to promote anoikis or cell survival after detachment (22), motility (23), CSC-like phenotypes (24), and chemotherapeutic resistance (25,26).…”

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confidence: 99%

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Maiuthed

Bhummaphan

Luanpitpong

et al. 2018

Journal of Biological Chemistry

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“…Nitric oxide can activate protein kinase B (AKT) and signal transducer and activator of transcription 3 (STAT3), which play key roles in multiple cellular processes including tumor glucose metabolism [32, 33]. To investigated whether they were involved in NO-mediated glycolysis.…”

Section: Resultsmentioning

confidence: 99%

iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer

Zhu

Hao

et al. 2017

Oncotarget

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Aerobic glycolysis is essential for tumor growth and survival. Activation of multiple carcinogenic signals contributes to metabolism reprogramming during malignant transformation of cancer. Recently nitric oxide has been noted to promote glycolysis but the mechanism remains elusive. We report here the dual role of nitric oxide in glycolysis: low/physiological nitric oxide (≤ 100 nM) promotes glycolysis for ATP production, oxidative defense and cell proliferation of ovary cancer cells, whereas excess nitric oxide (≥ 500 nM) inhibits it. Nitric oxide has a positive effect on glycolysis by inducing PKM2 nuclear translocation in an EGFR/ERK2 signaling-dependent manner. Moreover, iNOS induced by mild inflammatory stimulation increased glycolysis and cell proliferation by producing low doses of nitric oxide, while hyper inflammation induced iNOS inhibited it by producing excess nitric oxide. Finally, iNOS expression is abnormally increased in ovarian cancer tissues and is correlated with PKM2 expression. Overexpression of iNOS is associated with aggressive phenotype and poor survival outcome in ovarian cancer patients. Our study indicated that iNOS/NO play a dual role of in tumor glycolysis and progression, and established a bridge between iNOS/NO signaling pathway and EGFR/ERK2/PKM2 signaling pathway, suggesting that interfering glycolysis by targeting the iNOS/NO/PKM2 axis may be a valuable new therapeutic approach of treating ovarian cancer.

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“…Hence, CLIC1 acts as a regulator of ITGs. On the other hand, ITGs may influence MAPK and AKT signaling in tumors [35-37]. Thus, we measured the expression of PI3K/Akt, MAPK/ERK, MAPK/p38 and MAPK/JNK in orthotopically xenografted tumors.…”

Section: Discussionmentioning

confidence: 99%

CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways

Mao

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Chloride intracellular channel 1 (CLIC1), which is a member of the chloride channel protein family, is associated with various human tumors. Recent studies have shown that CLIC1 is involved in the occurrence and development of gastric cancer (GC). However, the exact mechanism remains unclear in GC. Methods: Effects of CLIC1 on the progression of GC in vivo and in vitro and the potential underlying mechanisms have been investigated by analysing 54 patients with GC, as well as human gastric cell lines SGC-7901 and MGC-803, utilizing proteomics, RT-PCR, Western blotting, flow cytometry, Cell invasion and migration assays and xenograft tumor models. Results: Our study shows that CLIC1 knockdown by targeted-siRNA markedly inhibits GC cell invasion and migration and induces apoptosis in vitro. In total, 54 differentially expressed proteins were identified in GC cells SGC-7901 after CLIC1 silencing by isobaric tags for relative isotope labeled and absolute quantitation (iTRAQ) technology, including integrin α1 (ITGα1) and ITGα3. The expression levels of ITGα3, ITGαv, ITGβ1 and Bcl-2 mRNA and protein were decreased significantly in GC cells after CLIC1 knockdown; ITGα1 and Fas were upregulated, but the level of survivin was not significantly different. GC growth and metabolism were decreased in vivo after CLIC1 silencing, but apoptosis was markedly increased. Further study showed that the expression levels of ITGα3, ITGαv and ITGβ1, as well as AKT-phosphorylation, ERK-phosphorylation and p38-phosphorylation, were reduced in vivo after CLIC1 knockdown, while ITGα1 was upregulated. Conclusions: We speculate that CLIC1 may play an important role in the progression of GC, and its mechanism may be related to the regulation of integrin family proteins, which leads to the sequential regulation of the PI3K/AKT, MAPK/ERK and MAPK/p38 pathways.

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Nitric oxide increases the migratory activity of non-small cell lung cancer cells via AKT-mediated integrin αv and β1 upregulation

Cited by 16 publications

References 40 publications

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

Nitric oxide promotes cancer cell dedifferentiation by disrupting an Oct4:caveolin-1 complex: A new regulatory mechanism for cancer stem cell formation

iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer

CLIC1 Promotes the Progression of Gastric Cancer by Regulating the MAPK/AKT Pathways

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