Cucurbitacin i inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells

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

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin-1 (CD133)-positive lung cancer cells. 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: Targeting STAT3 signaling in CD133-positive NSCLC cells with cucurbitacin I suppressed CSC-like properties and enhanced chemoradiotherapy response. The potential of cucurbitacin I should be verified further in future anti-CSC therapy.

Original languageEnglish
Pages (from-to)2970-2985
Number of pages16
JournalCancer
Volume117
Issue number13
DOIs
Publication statusPublished - Jul 1 2011
Externally publishedYes

Fingerprint

Cucurbitacins
Non-Small Cell Lung Carcinoma
STAT3 Transcription Factor
Neoplastic Stem Cells
B-Cell Chronic Lymphocytic Leukemia
Octamer Transcription Factors
Heterologous Transplantation
Survival
cucurbitacin I
Homeobox Genes
Chemoradiotherapy

Keywords

  • cancer stem cells
  • CD133
  • cucurbitacin
  • lung cancer
  • radiochemoresistance.
  • signal transducer and activator of transcription 3

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cucurbitacin i inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells. / Hsu, Han Shui; Huang, Pin I.; Chang, Yuh Lih; Tzao, Ching; Chen, Yi Wei; Shih, Hsin Chin; Hung, Shih Chieh; Chen, Yu Chih; Tseng, Ling Ming; Chiou, Shih Hwa.

In: Cancer, Vol. 117, No. 13, 01.07.2011, p. 2970-2985.

Research output: Contribution to journalArticle

Hsu, HS, Huang, PI, Chang, YL, Tzao, C, Chen, YW, Shih, HC, Hung, SC, Chen, YC, Tseng, LM & Chiou, SH 2011, 'Cucurbitacin i inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells', Cancer, vol. 117, no. 13, pp. 2970-2985. https://doi.org/10.1002/cncr.25869
Hsu, Han Shui ; Huang, Pin I. ; Chang, Yuh Lih ; Tzao, Ching ; Chen, Yi Wei ; Shih, Hsin Chin ; Hung, Shih Chieh ; Chen, Yu Chih ; Tseng, Ling Ming ; Chiou, Shih Hwa. / Cucurbitacin i inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells. In: Cancer. 2011 ; Vol. 117, No. 13. pp. 2970-2985.
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AU - Huang, Pin I.

AU - Chang, Yuh Lih

AU - Tzao, Ching

AU - Chen, Yi Wei

AU - Shih, Hsin Chin

AU - Hung, Shih Chieh

AU - Chen, Yu Chih

AU - Tseng, Ling Ming

AU - Chiou, Shih Hwa

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N2 - BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin-1 (CD133)-positive lung cancer cells. 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: Targeting STAT3 signaling in CD133-positive NSCLC cells with cucurbitacin I suppressed CSC-like properties and enhanced chemoradiotherapy response. The potential of cucurbitacin I should be verified further in future anti-CSC therapy.

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