Revisiting the role of ABC transporters in multidrug-resistant cancer

Robey, Robert W.; Pluchino, Kristen M.; Hall, Matthew D.; Fojo, Antonio Tito; Bates, Susan E.; Gottesman, Michael M.

doi:10.1038/s41568-018-0005-8

Cited by 1,328 publications

(1,392 citation statements)

References 160 publications

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“…Also on protein level, lower expression levels in ccRCC tissues were linked to inferior survival. 12 However, similar to BCRP/ABCG2, we found that decreased expression of MDR1/ABCB1 is associated with poor patient survival in ccRCC. For instance, the lactate transporter MCT4 is overexpressed in ccRCC and high MCT4 expression is linked to poor patient survival.…”

Section: Discussionsupporting

confidence: 54%

“…Moreover, due to a potential compensatory role because of functional redundancy, 12 we evaluated the multidrug resistance protein MDR1/ABCB1 expression and its association with patient survival. Moreover, due to a potential compensatory role because of functional redundancy, 12 we evaluated the multidrug resistance protein MDR1/ABCB1 expression and its association with patient survival.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Reustle

Fisel

Renner

et al. 2018

Intl Journal of Cancer

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The efflux transporter breast cancer resistance protein BCRP/ABCG2 is well-known for its contribution to multi-drug resistance in cancer. Its relevance in cancer biology independent from drug efflux remains largely elusive. Our study aimed at elucidating the biological relevance and regulatory mechanisms of BCRP/ABCG2 in clear cell renal cell carcinoma (ccRCC) and disease progression. Two independent ccRCC-cohorts [Cohort 1 (KIRC/TCGA): n = 453, Cohort 2: n = 64] were investigated to elucidate BCRP/ABCG2 mRNA and protein expression and their association with survival. The impact of BCRP/ABCG2 on response to sunitinib treatment was investigated in two independent sunitinib-treated ccRCC-cohorts based on mRNA levels. Moreover, underlying regulatory mechanisms for interindividual variability of BCRP/ABCG2 expression were systematically assessed. Owing to redundant functional properties, mRNA and protein expression of the multidrug resistance protein MDR1/ABCB1 were additionally evaluated in these cohorts. In independent ccRCC-cohorts, low BCRP/ABCG2 and MDR1/ABCB1 mRNA and protein expression were associated with severity (e.g., tumor stage) of ccRCC and poor cancer-specific survival. BCRP/ABCG2 and MDR1/ABCB1 mRNA expression were linked to decreased progression-free survival after sunitinib treatment. Germline and somatic variants influenced interindividual variability of BCRP/ABCG2 expression only moderately. miR-212-3p and miR-132-3p were identified to regulate BCRP/ABCG2 posttranscriptionally by interaction with the ABCG2 3'UTR as confirmed through reporter gene assays in RCC cell lines. In summary, BCRP/ABCG2 expression in ccRCC underlies considerable interindividual variability with impact on patient survival and response to sunitinib treatment. While germline or somatic genetic variants and DNA methylation cannot explain aberrant BCRP/ABCG2 expression, miR-212-3p and miR-132-3p were identified to contribute to posttranscriptional regulation of BCRP/ABCG2.

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Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Reustle

Fisel

Renner

et al. 2018

Intl Journal of Cancer

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“…P-gp transports one molecule of the substrate across the membrane, requiring two molecules of ATP to provide energy [37]. If the energy supply is insufficient, the function of P-gp is inhibited [38,39].…”

Section: Discussionmentioning

confidence: 99%

“…The basic structure of P-gp contains four core active regions, namely two hydrophilic nucleotide-binding domains (NBD) located in the cytoplasm that are responsible for binding to ATP and two hydrophobic transmembrane domains (TMD) that are responsible for binding to the substrate for P-gp transport [37,41]. For 4M2T, a corrected structure of mouse P-gp bound to QZ59-SSS, the corrected position of TMD4, which forms the frame of a portal for drug entry.…”

Section: Discussionmentioning

confidence: 99%

Targeting P-Glycoprotein: Nelfinavir Reverses Adriamycin Resistance in K562/ADR Cells

Wei

Meng

Sun

et al. 2018

Cell Physiol Biochem

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Background/Aims: The emergence of multidrug resistance (MDR) caused by P-glycoprotein (P-gp) overexpression is a serious obstacle to the treatment of chronic myelocytic leukemia. In recent years, some clinical trials have shown that nelfinavir (NFV), a traditional anti-HIV drug, has anti-cancer effects. Some researchers have also shown NFV might be a potential P-gp inhibitor. This study is aimed at investigating whether nelfinavir can act as an MDR-reversal drug and to clarify its molecular mechanism as well. Methods: K562 and K562/ADR cell lines were applied in the study. Cytotoxicity was detected by CCK-8 reagents. Cell apoptosis was detected by flow cytometry and inverted fluorescence microscopy to detect the binding of apoptotic dyes to cells. Western blot was used to detect the expression of proteins. Drug-protein molecular docking simulation by using Sybyl-x 2.0 software. Results: Non-toxic concentrations of NFV (1.25–5 μM) could reverse Adriamycin (ADR), colchicine, paclitaxel, and imatinib resistance of K562/ADR cells, with reversal indexes of up to 10.8, 7.4, 57, and 9.3, respectively. NFV inhibited P-gp efflux function, as evidenced by the significant increase in the intracellular accumulation of ADR and Rho-123, without affecting P-gp protein and mRNA expression levels. Further ATP content detection and molecular docking simulations showed that NFV could decrease intracellular ATP content and has a high affinity with the active functional regions of P-gp, respectively. When co-administered with ADR, NFV increased intracellular reactive oxygen species as well as blocked the ERK/Akt signaling pathway, leading to cell apoptosis. Conclusion: NFV inhibited P-gp function, decreased intracellular ATP content, and promoted cell apoptosis in K562/ADR cells, thereby reversing MDR. These findings encourage further animal and clinical MDR studies with a combination therapy consisting of NFV and chemotherapeutic drugs.

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“…Chemotherapy is usually used in the treatment of gastric cancer both in adjuvant and advanced settings [4]. Although chemotherapy has improved the survival of patients with gastric cancer, the development of multidrug resistance (MDR) is still a crucial problem leading to therapeutic failure and cancer-related death [5]. In addition, the underlying molecular mechanisms of MDR in gastric cancer remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway

Zeng

Liao

Zou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The development of multidrug resistance (MDR), which results in disease recurrence and metastasis, is a crucial obstacle to successful chemotherapy for patients with gastric cancer (GC). Long non-coding RNAs (lncRNAs) have been found to play various roles in cancer. This study aimed to investigate the effect of XLOC_006753 on the development of MDR in GC cells. Methods: The expression levels of XLOC_006753 in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell line) were assessed by qRT-PCR. Statistical analyses were conducted to determine the relationship between XLOC_006753 expression and clinical features and to assess the prognostic value of XLOC_006753 for overall survival and progression-free survival. Then, a CCK-8 assay was used to detect cell proliferation ability and chemosensitivity. Flow cytometry was used to detect cell cycle and cell apoptosis. A wound-healing assay and transwell assay were used to detect cell migration. The expression of markers for MDR, G1/S transition, epithelial–mesenchymal transition (EMT) and PI3K/ AKT/mTOR signaling pathway were examined by western blot. Results: XLOC_006753 was highly expressed in GC patients and MDR GC cell lines (SGC-7901/5-FU and SGC-7901/DDP cell lines), and its high expression was positively associated with metastasis, TNM stage, tumor size, and poor survival in GC patients. Moreover, XLOC_006753 was an independent prognostic biomarker of overall survival and progression-free survival for gastric cancer patients. Knocking down XLOC_006753 in the two MDR GC cell lines significantly inhibited cell proliferation, cell viability, cell cycle G1/S transition, and migration. XLOC_006753 knockdown also promoted apoptosis. Furthermore, western blots showed that XLOC_006753 knockdown decreased some markers of MDR, G1/S transition, and EMT expression, while increasing caspase9 expression and inhibiting the PI3K/AKT/mTOR signaling pathway in SGC-7901/5-FU and SGC-7901/DDP cells. Conclusion: High expression of XLOC_006753 promoted the development of MDR, which was activated by the PI3K/AKT/mTOR pathway in GC cells.

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Revisiting the role of ABC transporters in multidrug-resistant cancer

Cited by 1,328 publications

References 160 publications

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Characterization of the breast cancer resistance protein (BCRP/ABCG2) in clear cell renal cell carcinoma

Targeting P-Glycoprotein: Nelfinavir Reverses Adriamycin Resistance in K562/ADR Cells

Long Non-Coding RNA XLOC_006753 Promotes the Development of Multidrug Resistance in Gastric Cancer Cells Through the PI3K/AKT/mTOR Signaling Pathway

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