Cisplatin Selects for Multidrug-Resistant CD133+ Cells in Lung Adenocarcinoma by Activating Notch Signaling

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 1; pp. 406 - 416
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.01.2013
• Subjects: AC133 Antigen; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma of Lung; Animals; Antigens, CD - biosynthesis; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cisplatin - pharmacology; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Glycoproteins - biosynthesis; Humans; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Peptides; Pharmacology. Drug treatments; Pneumology; Receptors, Notch - drug effects; Signal Transduction - physiology; Transplantation, Heterologous; Tumors; Tumors of the respiratory system and mediastinum; Antineoplastic agent; Lung disease; Notch receptor; Respiratory disease; Lung cancer; Malignant tumor; Bronchopulmonary adenocarcinoma; In vitro; Bronchopulmonary; Cisplatin; Cell signaling; Signal transduction; Alkylating agent; Multiple resistance; Bronchus disease; Cell; Cancer; Platinum II Complexes
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-12-1733

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 γ-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. Cancer Res; 73(1); 406–16. ©2012 AACR.