caa a22 4500 445334622 CHVBK 20180317142750.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1245/s10434-011-1644-0 doi (NATIONALLICENCE)springer-10.1245/s10434-011-1644-0 Butylidenephthalide Suppresses Human Telomerase Reverse Transcriptase (TERT) in Human Glioblastomas [Elektronische Daten] [Po-Cheng Lin, Shinn-Zong Lin, Yi-Lin Chen, Jeng-Shou Chang, Li-Ing Ho, Po-Yen Liu, Li-Fu Chang, Yeu-Chern Harn, Shee-Ping Chen, Li-Yi Sun, Pi-Chun Huang, Jung-Ting Chein, Chang-Hai Tsai, Chii-Wen Chou, Horng-Jyh Harn, Tzyy-Wen Chiou] Background: Telomerase is widely expressed in most human cancers, but is almost undetectable in normal somatic cells and is therefore a potential drug target. Using the human telomerase promoter platform, the naturally occurring compound butylidenephthalide (BP) was selected for subsequent investigation of antitumor activity in vitro and in vivo. Methods: We treated human glioblastoma cells with BP and found a dose-dependent decrease in human telomerase reverse transcriptase (hTERT) mRNA expression and a concomitant increase in p16 and p21 expression. Because c-Myc and Sp1 are involved in transcriptional regulation of hTERT, the effect of BP on c-Myc and Sp1 expression was examined. Results: Using electrophoretic mobility shift assays and western blotting, we showed that BP represses hTERT transcriptional activity via downregulation of Sp1 expression. Using the telomerase repeat amplification protocol, an association between BP concentration and suppression of telomerase activity, induction of human glioblastoma senescence, and inhibition of cellular proliferation was identified. This was supported by a mouse xenograft model, in which BP repressed telomerase and inhibited tumor proliferation, resulting in tumor senescence. Overexpression of hTERT restored telomerase activity in human glioblastoma cells and overcame replicative senescence. Conclusions: These findings suggest that BP inhibits proliferation and induces senescence in human glioblastomas by downregulating hTERT expression and consequently telomerase activity. This is the first study to describe regulation of telomerase activity by BP in human glioblastomas. Society of Surgical Oncology, 2011 Lin Po-Cheng Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China aut Lin Shinn-Zong Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, Republic of China aut Chen Yi-Lin Graduate Institute of Biotechnology, National Ilan University, Ilan, Taiwan, Republic of China aut Chang Jeng-Shou Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China aut Ho Li-Ing Department of Respiratory Care, Veterans General Hospital-Taipei, Taipei, Taiwan, Republic of China aut Liu Po-Yen Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China aut Chang Li-Fu Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China aut Harn Yeu-Chern Graduate Institute of Networking and Multimedia, National Taiwain University, Taipei, Taiwan, Republic of China aut Chen Shee-Ping Buddhist Tzu Chi Stem Cells Center, Buddhist Tzu Chi Medical Center, Hualien, Taiwan, Republic of China aut Sun Li-Yi Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, Republic of China aut Huang Pi-Chun Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, Republic of China aut Chein Jung-Ting Departmeant of Medical Technology, China Medical University, Taichung, Taiwan, Republic of China aut Tsai Chang-Hai Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan, Republic of China aut Chou Chii-Wen Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, Republic of China aut Harn Horng-Jyh Department of Pathology, China Medical University Hospital, Taichung, Taiwan, Republic of China aut Chiou Tzyy-Wen Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China aut Annals of Surgical Oncology Springer-Verlag 18/12(2011-11-01), 3514-3527 1068-9265 18:12<3514 2011 18 10434 https://doi.org/10.1245/s10434-011-1644-0 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1245/s10434-011-1644-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Lin Po-Cheng Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Lin Shinn-Zong Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chen Yi-Lin Graduate Institute of Biotechnology, National Ilan University, Ilan, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chang Jeng-Shou Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Ho Li-Ing Department of Respiratory Care, Veterans General Hospital-Taipei, Taipei, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Liu Po-Yen Graduate Institute of Chinese Medicine, China Medical University, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chang Li-Fu Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Harn Yeu-Chern Graduate Institute of Networking and Multimedia, National Taiwain University, Taipei, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chen Shee-Ping Buddhist Tzu Chi Stem Cells Center, Buddhist Tzu Chi Medical Center, Hualien, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Sun Li-Yi Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Huang Pi-Chun Department of Stem Cell Applied Technology, Gwo Xi Stem Cell Applied Technology, Hsinchu, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chein Jung-Ting Departmeant of Medical Technology, China Medical University, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Tsai Chang-Hai Department of Pediatrics, China Medical University Hospital, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chou Chii-Wen Center for Neuropsychiatry and Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Harn Horng-Jyh Department of Pathology, China Medical University Hospital, Taichung, Taiwan, Republic of China aut NATIONALLICENCE 700 1- Chiou Tzyy-Wen Department of Life Science and Graduate Institute of Biotechnology, National Dong Hwa University, Hualien, Taiwan, Republic of China aut NATIONALLICENCE 773 0- Annals of Surgical Oncology Springer-Verlag 18/12(2011-11-01), 3514-3527 1068-9265 18:12<3514 2011 18 10434 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer