MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

Kaehler, Meike; Ruemenapp, Johanna; Gonnermann, Daniel; Nagel, Inga; Bruhn, Oliver; Haenisch, Sierk; Ammerpohl, Ole; Wesch, Daniela; Cascorbi, Ingolf; Bruckmueller, Henrike

doi:10.18632/oncotarget.21272

Cited by 22 publications

(23 citation statements)

References 62 publications

(74 reference statements)

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“…The upregulation of MDR proteins leads to excessive efflux of structurally and mechanistically diverse drugs and is an important mechanism of drug resistance ( 31 ). BCRP has been reported to mediate the resistance of many unrelated anticancer drugs, including doxorubicin ( 23 ), etoposide ( 32 ), imatinib ( 33 ), methotrexate ( 34 ), and mitoxantrone ( 23 , 35 ), among others ( 16 , 17 , 31 ). In keeping with this, our results showed the TAK-243–resistant BEND3 -knockout cells were cross-resistant to the known BCRP substrate mitoxantrone.…”

Section: Discussionmentioning

confidence: 99%

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

et al. 2021

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TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase I clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 ( BEND3 ), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ATP-binding cassette efflux transporter breast cancer resistance protein (BCRP; ABCG2) and reduced the intracellular levelsof TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origins. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.

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Section: Discussionmentioning

confidence: 99%

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

et al. 2021

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“…Using prediction by bioinformatics, it was discovered that the miR-222 sequence is closely associated with ALDH1, and may possibly be an upstream miRNA that regulates ALDH1 expression. miR-222 may cut the mRNA of ALDH1 to inhibit its translation (32). Regulation by miRNA promotes the upor downregulation of mRNA and plays an important role in the occurrence and development of diseases (33).…”

Section: Discussionmentioning

confidence: 99%

Aldehyde dehydrogenase 1, a target of miR‑222, is expressed at elevated levels in cervical cancer

et al. 2020

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The aim of the present study was to investigate the expression of microRNA-222 (miR-222) and aldehyde dehydrogenase 1 (ALDH1) in tissues and peripheral blood of cervical cancer patients, and to elucidate their underlying mechanisms of action. Tumor tissues and tumor-adjacent tissues were obtained from 33 cervical cancer patients and peripheral blood was obtained from these patients and 28 healthy subjects. The expression of miR-222 and ALDH1 mRNA was evaluated by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). To examine the levels of ALDH1 protein in tissues and blood, western blotting and ELISA were used. To confirm a direct interaction between miR-222 and ALDH1 mRNA, a dual luciferase reporter assay was performed. HeLA cells were transfected with agomiR-222 and expression of ALDH1 in the cells was measured by RT-qPCR and western blotting. MTT assay was preform to investigate the proliferation of HeLA cells. Expression of ALDH1 mRNA and protein was elevated in cervical cancer tissues and peripheral blood from patients compared with tumor-adjacent tissues and healthy controls, while the expression of miR-222 was reduced. Upregulation of miR-222 inhibited HeLA cell proliferation possibly due to a reduction in the expression of ALDH1. A dual luciferase reporter assay showed that miR-222 can bind with the 3'-untranslated seed region of ALDH1 mRNA to regulate its expression. miR-222 regulation of ALDH1 expression may play a role in the prevention of cervical cancer.

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“…It has been revealed that MRP1-3 lead to resistance to hydrophobic and anionic compounds, including several natural compounds, whereas MRP4, MRP5 and MRP8 efflux cyclic nucleotides (13,14). BCRP, a ubiquitous ABC transporter, has been shown to transport nucleoside drugs and nucleoside-monophosphate derivatives of clinically relevant nucleoside drugs (15,16). Moreover, these ABC transporters are highly expressed in various human cancer types and are closely associated with poor prognosis (17,18).…”

Section: Effect Of Sodium Butyrate On Abc Transporters In Lung Cancermentioning

confidence: 99%

Effect of sodium butyrate on ABC transporters in lung cancer A549 and colorectal cancer HCT116 cells

Shi

Xiang

et al. 2020

Oncol Lett

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Histone deacetylase (HDAC) inhibitors and DNA alkylators are effective components of combination chemotherapy. The aim of the present study was to investigate the possible mechanism of their synergism by detecting the effect of HDAC inhibitors on the expression levels of drug transporters that export DNA alkylators. It was demonstrated that the HDAC inhibitor sodium butyrate (NaB) induced the differential expression of multidrug resistant ATP-binding cassette (ABC) transporters in lung cancer and colorectal cancer cells. Specifically, NaB increased the mRNA expression levels of ABC subfamily B member 1 (ABCB1), ABCC10 and ABCC12, and protein expression levels of multidrug resistance-1 (MDR1), multidrug resistance-associated protein 7 (MRP7) and MRP9. Moreover, NaB decreased the expression levels of ABCC1, ABCC2 and ABCC3 mRNAs, as well as those of MRP1, MRP2 and MRP3 proteins. The molecular mechanism underlying this process was subsequently investigated. NaB decreased the expression of HDAC4, but not HDAC1, HDAC2 or HDAC3. In addition, NaB promoted histone H3 acetylation and methylation at lysine 9, as well as MDR1 acetylation, suggesting that acetylation and methylation may be involved in NaB-mediated ABC transporter expression. Thus, the present results indicated that the synergism of the HDAC inhibitors with the DNA alkylating agents may due to the inhibitory effect of MRPs by HDAC inhibitors. The findings also suggested the possibility of antagonistic effects following the combined treatment of HDAC inhibitors with MDR1 ligands.

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MicroRNA-212/ABCG2-axis contributes to development of imatinib-resistance in leukemic cells

Cited by 22 publications

References 62 publications

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

Aldehyde dehydrogenase 1, a target of miR‑222, is expressed at elevated levels in cervical cancer

Effect of sodium butyrate on ABC transporters in lung cancer A549 and colorectal cancer HCT116 cells

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