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

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126 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)406-416
Number of pages11
JournalCancer Research
Volume73
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Liu, Y. P., Yang, C. J., Huang, M. S., Yeh, C-T., Wu, A. T. H., Lee, Y. C., Lai, T. C., Lee, C. H., Hsiao, Y. W., Lu, J., Shen, C. N., Lu, P. J., & Hsiao, M. (2013). Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating notch signaling. Cancer Research, 73(1), 406-416. https://doi.org/10.1158/0008-5472.CAN-12-1733