caa a22 4500 445338385 CHVBK 20180317142803.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1245/s10434-010-1268-9 doi (NATIONALLICENCE)springer-10.1245/s10434-010-1268-9 mTOR Signaling is Involved in Indomethacin and Nimesulide Suppression of Colorectal Cancer Cell Growth via a COX-2 Independent Pathway [Elektronische Daten] [Yan-Jie Zhang, Yu-Jie Bao, Qiang Dai, Wen-Yan Yang, Peng Cheng, Li-Ming Zhu, Bi-Jun Wang, Fo-Hu Jiang] Background: Inhibition of mammalian target of rapamycin (mTOR) represents an attractive target for anticancer therapy, but its role in suppression of colorectal cancer (CRC) cell growth by cyclooxygenase-2 (COX-2) inhibitors is unclear. Here, we analyzed the effect of indomethacin (Indo, a nonselective COX-2 inhibitor) and nimesulide (Nim, a selective COX-2 inhibitor) on mTOR signaling in CRC cells in vitro and in vivo to determine the dependence of this effect on COX-2. Methods: Human CRC cell lines with varying COX-2 expression levels were treated with Indo and Nim. Western blot test was performed to detect mTOR-related components (mTOR, p70s6K, and 4EBP1), and cell viability, cell cycle, and apoptosis were assessed. HCT116 and SW1116 cells were injected into athymic nude mice to establish a CRC xenograft model. After treatment with Nim, tumor volume, mTOR signaling, and apoptosis were evaluated in this model. HT29 and SW1116 cells were also treated with Nim after transfection with COX-2-specific small interfering RNA (siRNA) to assess dependence of COX-2 on mTOR signaling under drug treatment. Results: Both Indo and Nim reduced mTOR signaling activity in CRC cells that differ in their COX-2 expression in vitro and in vivo. Additionally, Indo and Nim could reduce the mTOR signaling activity after COX-2 silencing in CRC cells. Conclusions: mTOR signaling is involved in Indo- and Nim-mediated suppression of CRC growth via a COX-2 independent pathway. This study unveils a novel mechanism through which COX-2 inhibitors exerts their anticancer effects and further emphasizes targeting mTOR signaling in anticancer therapy. Society of Surgical Oncology, 2010 Zhang Yan-Jie Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Bao Yu-Jie Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Dai Qiang Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Yang Wen-Yan Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Cheng Peng Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Zhu Li-Ming Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Wang Bi-Jun Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Jiang Fo-Hu Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut Annals of Surgical Oncology Springer-Verlag 18/2(2011-02-01), 580-588 1068-9265 18:2<580 2011 18 10434 https://doi.org/10.1245/s10434-010-1268-9 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1245/s10434-010-1268-9 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhang Yan-Jie Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Bao Yu-Jie Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Dai Qiang Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Yang Wen-Yan Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Cheng Peng Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Zhu Li-Ming Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Wang Bi-Jun Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 700 1- Jiang Fo-Hu Department of Digestion, No. 3 People's Hospital Affiliated to Shanghai Jiaotong University, School of Medicine, Shanghai, China aut NATIONALLICENCE 773 0- Annals of Surgical Oncology Springer-Verlag 18/2(2011-02-01), 580-588 1068-9265 18:2<580 2011 18 10434 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer