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- 학술저널
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- 2017.1
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Chemotherapy-induced cancer cell secretomes promote resistance due, in part, to a predominant glycolytic energy metabolism, which drives aggressive cancer cell proliferation. However, the characterization of these secretomes and the molecular events that associate them with acquired drug resistance remain poorly understood. In this study, we show that secretomes of cancer cells with high-level paclitaxel resistance stimulated cell proliferation and suppressed drug-induced apoptosis of drug-sensitive cells. We also found that drug (docetaxel)-stimulated induction of interferon-α (IFN-α), IFN-λ and tumor necrosis factor-α (TNF-α) release in drug-sensitive cells was lowered by these secretomes. The promotion of cell proliferation by paclitaxelresistant (PacR) cancer cell secretomes was associated, in part, with an increase in S phase of the cell cycle and downregulation of the cell death pathway that supports escape from apoptosis. In addition, we also found that the regulation of targeted glycolysis in PacR cancer cells alters the effects of the secretomes on cell growth, apoptosis, ATP generation and acquired drug resistance. Further study revealed that the deletion of FOXO3a transcription exacerbates glycolytic shift-induced apoptosis by rescuing TRAIL expression. By generating a docetaxel–cross-resistant PacR cancer cell line (PacR/DCT), we further clarified the role of FOXO3a in glycolysis-associated mediation of P-glycoprotein/ABCB1 hyperactivity that induces docetaxel cross-resistance.
These findings suggest that suppression of the cellular energy supply by targeting glycolysis may inhibit the multiplicity of acquired chemotherapy resistance. Therefore, the therapeutic inhibition of FOXO3a might direct glycolysis to induce apoptosis and overcome multidrug resistance in cancer cells.
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참고문헌 (24)
참고문헌 신청
Aldonza MB / 2015 / Suppression of MAPK signaling and reversal of mTOR-dependent MDR1-associated multidrug resistance by 21α-methylmelianodiol in lung cancer cells / PLoS O
Bae SY / 2015 / Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer / Oncotarget 6 : 10146 ~ 1
Binkhathlan Z / 2012 / P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer : current status and future perspectives / Curr Cance
Cancer Cell Line Encyclopedia Consortium / 2015 / Pharmacogenomic agreement between two cancer cell line data sets / Nature 528 : 84 ~ 87
Darzynkiewicz Z / 2008 / Analysis of apoptosis by cytometry using TUNEL assay / Methods 44 : 250 ~ 254
Bae SY / 2015 / Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer / Oncotarget 6 : 10146 ~ 1
Binkhathlan Z / 2012 / P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer : current status and future perspectives / Curr Cance
Cancer Cell Line Encyclopedia Consortium / 2015 / Pharmacogenomic agreement between two cancer cell line data sets / Nature 528 : 84 ~ 87
Darzynkiewicz Z / 2008 / Analysis of apoptosis by cytometry using TUNEL assay / Methods 44 : 250 ~ 254
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