Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells

Hung,Ming‑Szu; Chen,I‑Chuan; You,Liang; Jablons,David M.; Li,Ya‑Chin; Mao,Jian‑Hua; Xu,Zhidong; Hsieh,Meng‑Jer; Lin,Yu‑Ching; Yang,Cheng‑Ta; Liu,Shih‑Tung; Tsai,Ying‑Huang

doi:10.3892/or.2015.4324

Knockdown of Cul4A increases chemosensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells

Authors:
- Ming‑Szu Hung
- I‑Chuan Chen
- Liang You
- David M. Jablons
- Ya‑Chin Li
- Jian‑Hua Mao
- Zhidong Xu
- Meng‑Jer Hsieh
- Yu‑Ching Lin
- Cheng‑Ta Yang
- Shih‑Tung Liu
- Ying‑Huang Tsai
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Affiliations: Division of Thoracic Oncology, Department of Pulmonary and Critical Care Medicine, Chang Gung Memorial Hospital, Chiayi Branch, Chiayi 61363, Taiwan, R.O.C., Department of Emergency Medicine, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan, R.O.C., Thoracic Oncology Laboratory, Department of Surgery, Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA, Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA, Department of Respiratory Care, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C., Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan, R.O.C.
Published online on: October 2, 2015 https://doi.org/10.3892/or.2015.4324
Pages: 3187-3195

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Abstract

Cullin 4A (Cul4A) promotes oncogenesis through overexpression and then ubiquitination‑mediated proteolysis of tumor suppressors in various types of cancers. Transforming growth factor β‑induced (TGFBI) has been implicated as a tumor suppressor, which enhances gemcitabine chemosensitivity in lung cancer cells. The present study aimed to investigate the association of TGFBI and Cul4A and the mechanism by which Cul4A regulates TGFBI. In addition, we also evaluated the therapeutic value of Cul4A RNAi using adenoviral transfection of Cul4A RNAi in nude mouse xenograft models. We observed that knockdown of Cul4A was associated with increased sensitivity to gemcitabine through upregulation of TGFBI in lung cancer cells. Cul4A regulated TGFBI through direct interaction and then ubiquitin‑mediated protein degradation. In the nude mouse xenograft models, adenoviral transfection of Cul4A RNAi in combination with gemcitabine chemotherapy inhibited lung cancer tumor growth. As the result, combination of Cul4A RNAi with chemotherapy may provide a new approach to lung cancer treatment.

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