Dataset Information

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases.

ABSTRACT: The goal of this study was to define Na,K-ATPase ? and ? subunit isoform expression and isozyme composition in colorectal cancer cells and liver metastases. The ?1, ?3, and ?1 isoforms were the most highly expressed in tumor cells and metastases; in the plasma membrane of non-neoplastic cells and mainly in a cytoplasmic location in tumor cells. ?1?1 and ?3?1 isozymes found in tumor and metastatic cells exhibit the highest and lowest Na(+) affinity respectively and the highest K(+) affinity. Mesenchymal cell isozymes possess an intermediate Na(+) affinity and a low K(+) affinity. In cancer, these ions are likely to favor optimal conditions for the function of nuclear enzymes involved in mitosis, especially a high intra-nuclear K(+) concentration. A major and striking finding of this study was that in liver, metastasized CRC cells express the ?3?1 isozyme. Thus, the ?3?1 isozyme could potentially serve as a novel exploratory biomarker of CRC metastatic cells in liver.

SUBMITTER: Baker Bechmann M

PROVIDER: S-EPMC4731494 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases.

Baker Bechmann Marc M Rotoli Deborah D Morales Manuel M Maeso María Del Carmen Mdel C García María Del Pino Mdel P Ávila Julio J Mobasheri Ali A Martín-Vasallo Pablo P

Frontiers in physiology 20160129

The goal of this study was to define Na,K-ATPase α and β subunit isoform expression and isozyme composition in colorectal cancer cells and liver metastases. The α1, α3, and β1 isoforms were the most highly expressed in tumor cells and metastases; in the plasma membrane of non-neoplastic cells and mainly in a cytoplasmic location in tumor cells. α1β1 and α3β1 isozymes found in tumor and metastatic cells exhibit the highest and lowest Na(+) affinity respectively and the highest K(+) affinity. Mese ...[more]

PMID: 26858653

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Project description:Cardiac cells express more than one isoform of the Na, K-ATPase (NKA), the heteromeric enzyme that creates the Na(+) and K(+) gradients across the plasmalemma. Cardiac isozymes contain one catalytic ?-subunit isoform (?1, ?2, or ?3) associated with an auxiliary ?-subunit isoform (?1 or ?2). Past studies using biochemical approaches have revealed minor kinetic differences between isozymes formed by different ?-? isoform combinations; these results make it difficult to understand the physiological requirement for multiple isoforms. In intact cells, however, NKA enzymes operate in a more complex environment, which includes a substantial transmembrane potential. We evaluated the voltage dependence of human cardiac NKA isozymes expressed in Xenopus oocytes, and of native NKA isozymes in rat ventricular myocytes, using normal mammalian physiological concentrations of Na(+)o and K(+)o. We demonstrate that although ?1 and ?3 pumps are functional at all physiologically relevant voltages, ?2?1 pumps and ?2?2 pumps are inhibited by ?75% and ?95%, respectively, at resting membrane potentials, and only activate appreciably upon depolarization. Furthermore, phospholemman (FXYD1) inhibits pump function without significantly altering the pump's voltage dependence. Our observations provide a simple explanation for the physiological relevance of the ?2 subunit (?20% of total ? subunits in rat ventricle): they act as a reserve and are recruited into action for extra pumping during the long-lasting cardiac action potential, where most of the Na(+) entry occurs. This strong voltage dependence of ?2 pumps also helps explain how cardiotonic steroids, which block NKA pumps, can be a beneficial treatment for heart failure: by only inhibiting the ?2 pumps, they selectively reduce NKA activity during the cardiac action potential, leading to an increase in systolic Ca(2+), due to reduced extrusion through the Na/Ca exchanger, without affecting resting Na(+) and Ca(2+) concentrations.

Project description:Rationale: Patients with colorectal cancer die mainly due to liver metastases (CRC-LM). Although the tumor microenvironment (TME) plays an important role in tumor development and therapeutic response, our understanding of the individual TME components, especially cancer-associated fibroblasts (CAFs), remains limited. Methods: We analyzed CRC-LM CAFs and cancer cells by single-cell transcriptomics and used bioinformatics for data analysis and integration with related available single-cell and bulk transcriptomic datasets. We validated key findings by RT-qPCR, western blotting, and immunofluorescence. Results: By single-cell transcriptomic analysis of 4,397 CAFs from six CRC-LM samples, we identified two main CAF populations, contractile CAFs and extracellular matrix (ECM)-remodeling/pro-angiogenic CAFs, and four subpopulations with distinct phenotypes. We found that ECM-remodeling/pro-angiogenic CAFs derive from portal resident fibroblasts. They associate with areas of strong desmoplastic reaction and Wnt signaling in low-proliferating tumor cells engulfed in a stiff extracellular matrix. By integrating public single-cell primary liver tumor data, we propose a model to explain how different liver malignancies recruit CAFs of different origins to this organ. Lastly, we found that LTBP2 plays an important role in modulating collagen biosynthesis, ECM organization, and adhesion pathways. We developed fully human antibodies against LTBP2 that depleted LTBP2+ CAFs in vitro. Conclusion: This study complements recent reports on CRC-LM CAF heterogeneity at the single-cell resolution. The number of sequenced CAFs was more than one order of magnitude larger compared to existing data. LTBP2 targeting by antibodies might create opportunities to deplete ECM-remodeling CAFs in CRC-LMs. This might be combined with other therapies, e.g., anti-angiogenic compounds as already done in CRC. Moreover, we showed that in intrahepatic cholangiocarcinoma, in which ECM-remodeling CAF proportion is similar to that of CRC-LM, several genes expressed by ECM-remodeling CAFs, such as LTBP2, were associated with survival.

Dataset Information

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases.

Publications

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases.

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