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

Authors

  • Han-Shui Hsu MD, PhD,

    Corresponding author
    1. Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
    2. Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
    • Institute of Emergency and Critical Care Medicine and Institute of Clinical Medicine, National Yang-Ming University School of Medicine, No. 155, Sec. 2, Li-Nong Street, Taipei, Taiwan
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    • Fax: (011) 886-2-28746193

  • Pin-I Huang MD,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
    2. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Yuh-Lih Chang PhD,

    1. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, Republic of China
    2. Department of Education and Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
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  • Ching Tzao MD, PhD,

    1. Division of Thoracic Surgery, Tri-Service General Hospital, National Defense Medical Center; Taipei, Taiwan, Republic of China
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  • Yi-Wei Chen MD,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
    2. Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan
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  • Hsin-Chin Shih MD, PhD,

    1. Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China
    2. Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
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  • Shih-Chieh Hung MD, PhD,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
    2. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, Republic of China
    3. Department of Education and Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
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  • Yu-Chih Chen PhD,

    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
    2. Department of Education and Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
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  • Ling-Ming Tseng MD,

    1. Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
    2. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
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  • Shih-Hwa Chiou MD, PhD

    Corresponding author
    1. Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan Republic of China
    2. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, Republic of China
    3. Department of Education and Research, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
    • Institute of Emergency and Critical Care Medicine and Institute of Clinical Medicine, National Yang-Ming University School of Medicine, No. 155, Sec. 2, Li-Nong Street, Taipei, Taiwan
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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. Cancer 2011. © 2011 American Cancer Society.

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