title: The inhibitory effects of carnosic acid on cervical cancer cells growth by promoting apoptosis via ROS-regulated signaling pathway.
abstract: Cervical cancer has been the fourth most common cancer killing many women across the world. Carnosic acid (CA), as a phenolic diterpene, has been suggested to against cancer, exerting protective effects associated with inflammatory cytokines. It is aimed to demonstrate the therapeutic role of carnosic acid against cervical cancer and indicate its underlying molecular mechanisms. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) was performed to assess the possible anti-proliferative effects of carnosic acid. And also, colony formation was used to further estimate carnosic acid's ability in suppressing cervical cancer cells proliferation. Flow cytometry assays were performed here to indicate the alterations of cervical cancer cells cycle and the development of apoptosis. Western blot assays and RT-PCR were also applied to clarify the apoptosis-associated signaling pathways affected by reactive oxygen species (ROS) generation. And immunofluorescence was used to detect ROS-positive cells. In vivo experiments, CaSki xenograft model samples of nude mice were involved to further elucidate the effects of carnosic acid. In our results, we found that carnosic acid exerted anti-tumor ability in vitro supported by up-regulation of apoptosis and ROS production in cervical cancer cells. Also, acceleration of ROS led to the phospharylation of (c-Jun N-terminal kinase (JNK) and its-related signals, as well as activation of Endoplasmic Reticulum (ER) stress, promoting the progression of apoptosis via stimulating Caspase3 expression. The development and growth of xenograft tumors in nude mice were found to be inhibited by the administration of carnosic acid for five weeks. And the suppressed role of carnosic acid in proliferation of cervical cancer cells and apoptosis of nude mice with tumor tissues were observed in our study. Taken together, our data indicated that carnosic acid resulted in apoptosis both in vitro and vivo experiments via promoting ROS and activating JNK signaling pathways in human cervical cancer cells, which supplied a potential therapy for the application of carnosic acid in clinical treatment.
authors.affiliation: Department of gynecology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan 450052, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Su
authors.affiliation: Department of gynecology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan 450052, PR China.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Wang
authors.affiliation: Department of gynecology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan 450052, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of gynecology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan 450052, PR China.
authors.forename: Yu-Jie
authors.initials: YJ
authors.lastname: Cai
authors.affiliation: Department of gynecology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan 450052, PR China.
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of gynecology, The First Affiliated Hospital of Zhengzhou University, 1 Jianshe Road, Zhengzhou City, Henan 450052, PR China. Electronic address: zhaoqian450052@139.com.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008819:Mice, Nude; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; C018381:salvin
keywords: Apoptosis; Carnosic acid; Cervical cancer; ROS generation