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Orthotopic Transplantation of Syngeneic Lung Adenocarcinoma Cells to Study PD-L1 Expression
Published on: January 19, 2019
The alpha1 subunit of the sodium pump could represent a novel target to combat non-small cell lung cancers
T Mijatovic1, I Roland, E Van Quaquebeke
1Unibioscreen SA, 40 Avenue Joseph Wybran, 1070 Brussels, Belgium.
Abstract:
With an overall 5 year survival rate as low as 15% for non-small cell lung cancer (NSCLC), even with surgical intervention and the use of newer molecules in adjuvant chemotherapy, there is an urgent need for new biological targets and associated novel anti-cancer agents. The present study was undertaken to evaluate the potential of the Na(+)/K(+)-ATPase alpha1 subunit as a novel target in NSCLC and revealed that alpha1 expression is markedly higher in a significant proportion of NSCLC clinical samples compared to normal lung tissue. Furthermore, reduction in alpha1 expression in A549 NSCLC cells by anti-alpha1 siRNA resulted in markedly impaired proliferation and migration of these cancer cells. Finally, of three cardenolides investigated, UNBS1450, which is known to bind to Na(+)/K(+)-ATPase and displays potent anti-tumour activity in vivo in experimental models of human NSCLCs, is the most potent inhibitor of Na(+)/K(+)-ATPase isozymes (alpha1beta1, alpha2beta1 and alpha3beta1), most strikingly of alpha1beta1. This was reflected in the compound's more potent anti-proliferative activity in all NSCLC cell lines evaluated (A549, Cal-12T, NCI-H727 and A427); the first three of which over-express alpha1. The marked impairment in A549 NSCLC cell proliferation and migration, and resulting similar morphology following anti-alpha1 siRNA or UNBS1450 treatment, was associated with features of abnormal cytokinesis, mediated in the case of UNBS1450 by disorganization of the actin cytoskeleton. Collectively these data strongly suggest that targeting the Na(+)/K(+)-ATPase alpha1 using specific cardenolides could represent a novel means to combat certain NSCLCs.
Insights
Targeting the Na(+)/K(+)-ATPase alpha1 subunit shows promise for treating non-small cell lung cancer (NSCLC). Inhibiting this target with cardenolides like UNBS1450 impaired cancer cell proliferation and migration, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) has a poor 5-year survival rate, necessitating novel therapeutic targets and agents.
- The Na(+)/K(+)-ATPase alpha1 subunit is increasingly recognized for its role in cancer progression.
Purpose of the Study:
- To investigate the Na(+)/K(+)-ATPase alpha1 subunit as a potential therapeutic target in NSCLC.
- To evaluate the efficacy of cardenolides, specifically UNBS1450, in targeting this subunit for NSCLC treatment.
Main Methods:
- Analysis of alpha1 subunit expression in NSCLC clinical samples and cell lines.
- Utilizing anti-alpha1 siRNA to reduce alpha1 expression in A549 NSCLC cells.
- Assessing the anti-proliferative and anti-migratory effects of UNBS1450 on NSCLC cells.
- Investigating the mechanism of action, including effects on actin cytoskeleton and cytokinesis.
Main Results:
- Alpha1 subunit expression was significantly higher in NSCLC samples compared to normal lung tissue.
- Reduction of alpha1 expression via siRNA impaired NSCLC cell proliferation and migration.
- UNBS1450 demonstrated potent inhibition of Na(+)/K(+)-ATPase isozymes, particularly alpha1beta1.
- UNBS1450 exhibited significant anti-proliferative activity across various NSCLC cell lines, correlating with alpha1 overexpression.
- UNBS1450 treatment led to impaired proliferation, migration, abnormal cytokinesis, and actin cytoskeleton disorganization.
Conclusions:
- The Na(+)/K(+)-ATPase alpha1 subunit is a promising therapeutic target for NSCLC.
- Specific cardenolides, such as UNBS1450, show potential as novel anti-cancer agents for NSCLC by targeting the alpha1 subunit.
- Targeting the Na(+)/K(+)-ATPase alpha1 subunit offers a novel strategy for combating certain NSCLC types.
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