Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells.
Abstract | BACKGROUND: METHODS: CD133-positive and CD133-negative NSCLC-derived cells were isolated from 7 patients with NSCLC. CD133-positive NSCLC cells that were treated with or without cucurbitacin I were evaluated for their expression of phosphorylated STAT3 (p-STAT3), tumorigenicity, stemness properties, and resistance to chemotherapeutic drugs and ionizing radiation. RESULTS: Compared with parental or CD133-negative NSCLC cells, CD133-positive NSCLC cells had greater tumorigenicity, greater radioresistance, and higher expression of octamer-binding transcription factor 4 (Oct-4), Nanog homeobox, and sex-determining region Y, box 2 (Sox2) at high p-STAT3 levels. Cucurbitacin I treatment at 100 nM effectively abrogated STAT3 activation, tumorigenic capacity, sphere formation ability, radioresistance, and chemoresistance in CD133-positive NSCLC cells. Microarray data suggested that cucurbitacin I inhibited the stemness gene signature of CD133-positive NSCLC cells and facilitated the differentiation of CD133-positive NSCLC cells into CD133-negative NSCLC cells. It is noteworthy that 150 nM cucurbitacin I effectively blocked STAT3 signaling and downstream survival targets, such as B-cell chronic lymphocytic leukemia/ lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-xL) expression and induced apoptosis in CD133-positive NSCLC cells. Finally, xenotransplantation experiments revealed that cucurbitacin I plus radiotherapy or chemotherapeutic drugs significantly suppressed tumorigenesis and improved survival in NSCLC-CD133-positive-transplanted, immunocompromised mice. CONCLUSIONS:
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Authors | Han-Shui Hsu, Pin-I Huang, Yuh-Lih Chang, Ching Tzao, Yi-Wei Chen, Hsin-Chin Shih, Shih-Chieh Hung, Yu-Chih Chen, Ling-Ming Tseng, Shih-Hwa Chiou |
Journal | Cancer
(Cancer)
Vol. 117
Issue 13
Pg. 2970-85
(Jul 01 2011)
ISSN: 1097-0142 [Electronic] United States |
PMID | 21225866
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 American Cancer Society. |
Chemical References |
- AC133 Antigen
- Antigens, CD
- Glycoproteins
- Homeodomain Proteins
- NANOG protein, human
- Nanog Homeobox Protein
- Octamer Transcription Factor-3
- PROM1 protein, human
- Peptides
- Prom1 protein, mouse
- Proto-Oncogene Proteins c-bcl-2
- SOX2 protein, human
- SOXB1 Transcription Factors
- STAT3 Transcription Factor
- Triterpenes
- bcl-X Protein
- cucurbitacin I
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Topics |
- AC133 Antigen
- Aged
- Animals
- Antigens, CD
(analysis)
- Apoptosis
(drug effects, genetics)
- Blotting, Western
- Carcinoma, Non-Small-Cell Lung
(drug therapy, metabolism, pathology, radiotherapy)
- Cell Proliferation
- Cell Separation
- Drug Resistance, Neoplasm
- Enzyme-Linked Immunosorbent Assay
- Female
- Fluorescent Antibody Technique
- Glycoproteins
(analysis)
- Homeodomain Proteins
(biosynthesis, genetics)
- Humans
- Lung Neoplasms
(drug therapy, metabolism, pathology, radiotherapy)
- Male
- Mice
- Middle Aged
- Nanog Homeobox Protein
- Neoplasm Metastasis
- Neoplasm Transplantation
- Neoplastic Stem Cells
(drug effects, metabolism, radiation effects)
- Octamer Transcription Factor-3
(biosynthesis, genetics)
- Peptides
(analysis)
- Proto-Oncogene Proteins c-bcl-2
(genetics)
- Radiation Tolerance
- SOXB1 Transcription Factors
(biosynthesis, genetics)
- STAT3 Transcription Factor
(antagonists & inhibitors, metabolism)
- Signal Transduction
(drug effects)
- Triterpenes
(pharmacology)
- Tumor Cells, Cultured
- bcl-X Protein
(genetics)
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