title: Tumorigenesis of smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone is related to its ability to stimulate thromboxane synthase and enhance stemness of non-small cell lung cancer stem cells.
abstract: Lung cancer stem cells (LCSCs) play a critical role in lung cancer development, however, it is unknown whether thromboxane synthase (TXS) plays a role in the maintenance of LCSCs stemness. This study aimed to determine the in vivo role of TXS in lung cancer induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a smoking carcinogen. Results showed that ozagrel, a TXS blocker, suppressed NNK-induced lung tumors in mice. The expressions of CD133 and ALDH1A1 were positively associated with TXS. Similar results were observed in human NSCLC tumor samples. NNK significantly stimulated TXS and enhanced the generation of LCSCs, evident by the upregulation of CD133 and ALDH1A1 expression, and the increase in the number and size of tumor spheres. NNK also promoted the expression of LCSC-related molecules including β-catenin and Nanog. All these NNK-mediated effects could be offset by ozagrel. In the colony formation assay, NNK increased whereas ozagrel decreased the number of colonies. Collectively, LCSCs and TXS participate in NNK-induced lung cancer. Our data suggest that TXS is a promising therapeutic target as it is a key molecular in NNK-mediated stemness of LCSCs.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong; Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong.
authors.forename: Shucai
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong.
authors.forename: Ming-Yue
authors.initials: MY
authors.lastname: Li
authors.affiliation: The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors.forename: Runyue
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong.
authors.forename: Calvin S H
authors.initials: CS
authors.lastname: Ng
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong.
authors.forename: Innes Y P
authors.initials: IY
authors.lastname: Wan
authors.affiliation: Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Long
authors.affiliation: Department of Respiratory Medicine, Affiliated Hospital of Guang Dong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Respiratory Medicine, Affiliated Hospital of Guang Dong Medical University, Zhanjiang, Guangdong, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Peking University Shenzhen Hospital, Shenzhen, Guangdong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong.
authors.forename: Tony S K
authors.initials: TS
authors.lastname: Mok
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Underwood
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin N.T., Hong Kong. Electronic address: gchen@cuhk.edu.hk.
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
mesh_terms: D002273:Carcinogens / Q000633:toxicity*; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009602:Nitrosamines / Q000633:toxicity*; D013930:Thromboxane-A Synthase / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: C495270:CTNNB1 protein, human; D002273:Carcinogens; D009602:Nitrosamines; D051176:beta Catenin; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D013930:Thromboxane-A Synthase
keywords: Lung cancer; NNK; Smoking; Stem cells; Thromboxane