title: Selective β2-AR Blockage Suppresses Colorectal Cancer Growth Through Regulation of EGFR-Akt/ERK1/2 Signaling, G1-Phase Arrest, and Apoptosis.
abstract: The stress-upregulated catecholamines-activated β1- and β2-adrenergic receptors (β1/2-ARs) have been shown to accelerate the progression of cancers such as colorectal cancer (CRC). We investigated the underlying mechanism of the inhibition of β1/2-ARs signaling for the treatment of CRC and elucidated the significance of β2-AR expression in CRC in vitro and in clinical samples. The impacts of β1/2-AR antagonists in CRC in vitro and CRC-xenograft in vivo were examined. We found that repression of β2-AR but not β1-AR signaling selectively suppressed cell viability, induced G1-phase cell cycle arrest, caused both intrinsic and extrinsic pathways-mediated apoptosis of specific CRC cells and inhibited CRC-xenograft growth in vivo. Moreover, the expression of β2-AR was not consistent with the progression of CRC in vitro or in clinical samples. Our data evidence that the expression profiles, signaling, and blockage of β2-AR have a unique pattern in CRC comparing to other cancers. β2-AR antagonism selectively suppresses the growth of CRC accompanying active β2-AR signaling, which potentially carries wild-type KRAS, in vitro and in vivo via the inhibition of β2-AR transactivated EFGR-Akt/ERK1/2 signaling pathway. Thus, β2-AR blockage might be a potential therapeutic strategy for combating the progressions of β2-AR-dependent CRC.
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chin
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Jhy-Ming
authors.initials: JM
authors.lastname: Li
authors.affiliation: Department of Anatomic Pathology, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Kam-Fai
authors.initials: KF
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Kuan-Chieh
authors.initials: KC
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Hsiao-Ching
authors.initials: HC
authors.lastname: Lai
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chih-Chung
authors.initials: CC
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.|Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yi-Hung
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chung-Sheng
authors.initials: CS
authors.lastname: Shi
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001262:Atenolol / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045304:Cytochromes c / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015870:Gene Expression; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000145:classification / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D018797:Cell Cycle Proteins; D011412:Propanolamines; D019253:Proto-Oncogene Proteins c-bcl-2; D011943:Receptors, Adrenergic, beta; C026777:ICI 118551; D001262:Atenolol; D045304:Cytochromes c; D011433:Propranolol; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt