Oncogenic PITX2 facilitates tumor cell drug resistance by inverse regulation of hOCT3/SLC22A3 and ABC drug transporters in colon and kidney cancers
Abstract
Oncogenic pituitary homeobox 2 (PITX2), a de facto master regulator of developmental organ asymmetry, previously upregulated multidrug resistance (MDR) P-glycoprotein ABCB1 in A498 renal cell carcinoma (RCC) cells. The role of PITX2 isoforms in MDR cancers was investigated. Data mining correlated elevated PITX2 in >30% of cancers analyzed, maximally in colon (4.4-fold), confirmed in co-immunostaining of colon and renal cancer microarrays wherein ABCB1 concomitantly increased in RCC. Drug-resistant colorectal adenocarcinoma Colo320DM cells exhibited increased nuclear PITX2 (40-fold), PITX2 promoter activity (27-fold) and ABCB1 (8000-fold) compared to drug-sensitive Colo205. ABCB1 inhibitor PSC833/valspodar or PITX2 siRNA reversed doxorubicin resistance. Nuclei from Colo320DM and A498 cells harbored PITX2A/B1 and PITX2A/B1/B2/Cα/Cβ, respectively. ChIP-qPCR evidenced PITX2 promoter binding in drug exporters ABCB1, ABCC1, ABCG2 and importer hOCT3/SLC22A3. In A498, 786-O, Caki-1, Colo320DM, and Caco2 cells, PITX2 siRNA diminished exporters, increased hOCT3/SLC22A3 expression and activity, and reverted vincristine resistance. Heterologous PITX2 expression induced ABCB1, repressed hOCT3/SLC22A3, enhanced vincristine resistance and diminished proliferation inhibition wherein PITX2A and PITX2C were most effective. Furthermore, PITX2 activity and MDR depended on phosphorylation by GSK3 in A498 cells. Conclusively, oncogenic PITX2 limits sensitizing drug uptake and potentiates cytoprotective drug efflux, contributing to MDR phenotype.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The occurrence of multidrug resistance of cancer cells reduces the efficacy of chemotherapeutic drugs and has become the most crucial reason for the failure of hepatocellular carcinoma treatment.
“Especially, the occurrence of multidrug resistance (MDR) of cancer cells can reduce the efficacy of chemotherapeutic drugs,6,7 which has become the most crucial reason for the failure of HCC treatment.”
Multidrug resistance contributes to reduced sensitivity of cancer cells to chemotherapeutic drugs, mainly owing to over-expression of drug efflux transporters.
“Multidrug resistance (MDR) has emerged to be a major hindrance in cancer therapy, which contributes to the reduced sensitivity of cancer cells toward chemotherapeutic drugs mainly owing to the over-expression of drug efflux transporters.”
The citation lists haven’t been fetched yet
References 51 · Cited by 28
- Authors
- Lee, W.-K., & Thévenod, F.
- Affiliations
- Witten/Herdecke University (DE)
- Corresponding author
- Lee, Wing-Kee
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 449
- Pages
- 237-251
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2912072373
- Cited by
- 28
- References
- 51
- Citations by year
- 2025: 7 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 7 · 2020: 7 · 2019: 1
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Intramural Research Program of Witten/Herdecke University
- Westermann-Westerdorp Foundation
- Deutsche Forschungsgemeinschaft
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Antibiotic Resistance in Bacteria
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- PITX2, multidrug resistance, P-glycoprotein, ABC transporters, colon cancer, renal cell carcinoma, drug resistance, GSK3 phosphorylation, doxorubicin resistance, vincristine resistance, ABCG2, MRP1, drug efflux, drug uptake
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily G, Member 2, Homeobox Protein PITX2, Organic Cation Transporter 3, Antineoplastic Agents, Colonic Neoplasms, Doxorubicin, Humans, Kidney Neoplasms, Neoplasm Proteins, Phosphorylation, Transcription Factors, Vincristine, Signal Transduction, Gene Expression Regulation, Neoplastic, Homeodomain Proteins, Drug Resistance, Multiple, Caco-2 Cells, Drug Resistance, Neoplasm, Organic Cation Transport Proteins, Glycogen Synthase Kinase 3, Cell Proliferation, ATP Binding Cassette Transporter 1
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
