Knockdown of Cul4A increases chemosensitivity to gemcitabine  through upregulation of TGFBI in lung cancer cells.
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.
Ming-Szu
MS
Hung
I-Chuan
IC
Chen
Liang
L
You
David M
DM
Jablons
Ya-Chin
YC
Li
Jian-Hua
JH
Mao
Zhidong
Z
Xu
Meng-Jer
MJ
Hsieh
Yu-Ching
YC
Lin
Cheng-Ta
CT
Yang
Shin-Tung
ST
Liu
Ying-Huang
YH
Tsai
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine; D000099222:betaIG-H3 Protein
D044842:Cullin Proteins; D003841:Deoxycytidine; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta; D000093542:Gemcitabine; D000099222:betaIG-H3 Protein; C114234:CUL4A protein, human