Reference - Detail
| RRC ID | 68123 |
|---|---|
| Author | Ohya S, Kajikuri J, Endo K, Kito H, Elboray EE, Suzuki T. |
| Title | Ca2+ -activated K+ channel KCa 1.1 as a therapeutic target to overcome chemoresistance in three-dimensional sarcoma spheroid models. |
| Journal | Cancer Sci |
| Abstract |
The large-conductance Ca2+ -activated K+ channel KCa 1.1 plays a pivotal role in tumor development and progression in several solid cancers. The three-dimensional (3D) in vitro cell culture system is a powerful tool for cancer spheroid formation, and mimics in vivo solid tumor resistance to chemotherapy in the tumor microenvironment (TME). KCa 1.1 is functionally expressed in osteosarcoma and chondrosarcoma cell lines. KCa 1.1 activator-induced hyperpolarizing responses were significantly larger in human osteosarcoma MG-63 cells isolated from 3D spheroid models compared with in those from adherent 2D monolayer cells. The present study investigated the mechanisms underlying the upregulation of KCa 1.1 and its role in chemoresistance using a 3D spheroid model. KCa 1.1 protein expression levels were significantly elevated in the lipid-raft-enriched compartments of MG-63 spheroids without changes in its transcriptional level. 3D spheroid formation downregulated the expression of the ubiquitin E3 ligase FBXW7, which is an essential contributor to KCa 1.1 protein degradation in breast cancer. The siRNA-mediated inhibition of FBXW7 in MG-63 cells from 2D monolayers upregulated KCa 1.1 protein expression. Furthermore, a treatment with a potent and selective KCa 1.1 inhibitor overcame the chemoresistance of the MG-63 and human chondrosarcoma SW-1353 spheroid models to paclitaxel, doxorubicin, and cisplatin. Among several multidrug resistance ATP-binding cassette transporters, the expression of the multidrug resistance-associated protein MRP1 was upregulated in both spheroids and restored by the inhibition of KCa 1.1. Therefore, the pharmacological inhibition of KCa 1.1 may be an attractive new strategy for acquiring resistance to chemotherapeutic drugs in the TME of KCa 1.1-positive sarcomas. |
| Volume | 112(9) |
| Pages | 3769-3783 |
| Published | 2021-9-1 |
| DOI | 10.1111/cas.15046 |
| PMID | 34181803 |
| PMC | PMC8409426 |
| MeSH | Antineoplastic Agents / pharmacology Bone Neoplasms / metabolism* Bone Neoplasms / pathology Cell Line, Tumor Cell Survival / drug effects Cisplatin / pharmacology Doxorubicin / pharmacology Drug Resistance, Neoplasm / drug effects* Drug Resistance, Neoplasm / genetics* F-Box-WD Repeat-Containing Protein 7 / genetics F-Box-WD Repeat-Containing Protein 7 / metabolism Humans Indoles / pharmacology Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / antagonists & inhibitors Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism* Osteosarcoma / metabolism* Osteosarcoma / pathology Paclitaxel / pharmacology Potassium Channel Blockers / pharmacology RNA, Small Interfering / genetics Spheroids, Cellular / metabolism* Transfection Tumor Microenvironment / drug effects Tumor Microenvironment / genetics Up-Regulation / genetics* |
| IF | 4.966 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | MG-63(RCB1890) |