Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating notch signaling

Yu Peng Liu, Chih Jen Yang, Ming Shyan Huang, Chi-Tai Yeh, Alexander T H Wu, Yu Cheng Lee, Tsung Ching Lai, Chien Hsin Lee, Ya Wen Hsiao, Jean Lu, Chia Ning Shen, Pei Jung Lu, Michael Hsiao

研究成果: 雜誌貢獻文章

120 引文 (Scopus)

摘要

Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133+ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133+ cells has not been investigated methodically. In this study, we revealed that CD133+ lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC20) was sufficient to enrich CD133+ cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133+ cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the g-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1- alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133+ cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133+ cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133+ cell number. Together, our results showed that cisplatin induces the enrichment of CD133 + cells, leading to multidrug resistance by the activation of Notch signaling.
原文英語
頁(從 - 到)406-416
頁數11
期刊Cancer Research
73
發行號1
DOIs
出版狀態已發佈 - 一月 1 2013

指紋

Cisplatin
Paclitaxel
Drug Resistance
Doxorubicin
Lung Neoplasms
Therapeutics
Adenocarcinoma of lung
Recurrence
Drug Therapy
Neoplasms
Amyloid Precursor Protein Secretases
Multiple Drug Resistance
Platinum
Non-Small Cell Lung Carcinoma
Small Interfering RNA
DNA Damage
Up-Regulation
Stem Cells
Cell Count
Immunohistochemistry

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

引用此文

Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating notch signaling. / Liu, Yu Peng; Yang, Chih Jen; Huang, Ming Shyan; Yeh, Chi-Tai; Wu, Alexander T H; Lee, Yu Cheng; Lai, Tsung Ching; Lee, Chien Hsin; Hsiao, Ya Wen; Lu, Jean; Shen, Chia Ning; Lu, Pei Jung; Hsiao, Michael.

於: Cancer Research, 卷 73, 編號 1, 01.01.2013, p. 406-416.

研究成果: 雜誌貢獻文章

Liu, YP, Yang, CJ, Huang, MS, Yeh, C-T, Wu, ATH, Lee, YC, Lai, TC, Lee, CH, Hsiao, YW, Lu, J, Shen, CN, Lu, PJ & Hsiao, M 2013, 'Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating notch signaling', Cancer Research, 卷 73, 編號 1, 頁 406-416. https://doi.org/10.1158/0008-5472.CAN-12-1733
Liu, Yu Peng ; Yang, Chih Jen ; Huang, Ming Shyan ; Yeh, Chi-Tai ; Wu, Alexander T H ; Lee, Yu Cheng ; Lai, Tsung Ching ; Lee, Chien Hsin ; Hsiao, Ya Wen ; Lu, Jean ; Shen, Chia Ning ; Lu, Pei Jung ; Hsiao, Michael. / Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating notch signaling. 於: Cancer Research. 2013 ; 卷 73, 編號 1. 頁 406-416.
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abstract = "Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133+ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133+ cells has not been investigated methodically. In this study, we revealed that CD133+ lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC20) was sufficient to enrich CD133+ cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133+ cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the g-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1- alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133+ cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133+ cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133+ cell number. Together, our results showed that cisplatin induces the enrichment of CD133 + cells, leading to multidrug resistance by the activation of Notch signaling.",
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AU - Wu, Alexander T H

AU - Lee, Yu Cheng

AU - Lai, Tsung Ching

AU - Lee, Chien Hsin

AU - Hsiao, Ya Wen

AU - Lu, Jean

AU - Shen, Chia Ning

AU - Lu, Pei Jung

AU - Hsiao, Michael

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AB - Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer, but recurrence occurs in most patients. Recent evidence suggests that CD133+ cells are the cause of drug resistance and tumor recurrence. However, the correlation between chemotherapy and regulation of CD133+ cells has not been investigated methodically. In this study, we revealed that CD133+ lung cancer cells labeled by a human CD133 promoter-driven GFP reporter exhibited drug resistance and stem cell characteristics. Treatment of H460 and H661 cell lines with low-dose cisplatin (IC20) was sufficient to enrich CD133+ cells, to induce DNA damage responses, and to upregulate ABCG2 and ABCB1 expression, which therefore increased the cross-resistance to doxorubicin and paclitaxel. This cisplatin-induced enrichment of CD133+ cells was mediated through Notch signaling as judged by increased levels of cleaved Notch1 (NICD1). Pretreatment with the g-secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-1- alanyl]-S-phenylglycine t-butyl ester (DAPT), or Notch1 short hairpin RNAs (shRNA) remarkably reduced the cisplatin-induced enrichment of CD133+ cells and increased the sensitivity to doxorubicin and paclitaxel. Ectopic expression of NICD1 reversed the action of DAPT on drug sensitivity. Immunohistochemistry showed that CD133+ cells were significantly increased in the relapsed tumors in three of six patients with lung cancer who have received cisplatin treatment. A similar effect was observed in animal experiments as cisplatin treatment increased Notch1 cleavage and the ratio of CD133+ cells in engrafted tumors. Intratumoral injection of DAPT with cisplatin treatment significantly reduced CD133+ cell number. Together, our results showed that cisplatin induces the enrichment of CD133 + cells, leading to multidrug resistance by the activation of Notch signaling.

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