title: Costunolide and dehydrocostuslactone combination treatment inhibit breast cancer by inducing cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 pathway.
abstract: Our previous studies demonstrated that volatile oil from saussurea lappa root (VOSL), rich in two natural sesquiterpene lactones, costunolide (Cos) and dehydrocostuslactone (Dehy), exerts better anti-breast cancer efficacy and lower side effects than Cos or Dehy alone in vivo, however, their anti-cancer molecular mechanisms were still unknown. In this study, we investigated the underlying mechanisms of Cos and Dehy combination treatment (CD) on breast cancer cells through proteomics technology coupled with Western blot validation. Ingenuity Pathways Analysis (IPA) results based on the differentially expressed proteins revealed that both VOSL and CD affect the 14-3-3-mediated signaling, c-Myc mediated apoptosis signaling and protein kinase A (PKA) signaling. Western blot coupled with cell cycle and apoptosis analysis validated the results of proteomics analysis. Cell cycle arrest and apoptosis were induced in a dose-dependent manner, and the expressions of p53 and p-14-3-3 were significantly up-regulated, whereas the expressions of c-Myc, p-AKT, p-BID were significantly down-regulated, furthermore, the ratio of BAX/BCL-2 were significantly increased in breast cancer cells after CD and VOSL treatment. The findings indicated that VOSL and CD could induce breast cancer cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 signaling pathways and may be novel effective candidates for breast cancer treatment.
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.|School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Zhangxiao
authors.initials: Z
authors.lastname: Peng
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Lin
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Chunying
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Weidan
authors.initials: W
authors.lastname: Ji
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital &National Center of Liver Cancer, Second Military Medical University, Shanghai 200438, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000494:pharmacology; D005260:Female; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009822:Oils, Volatile / Q000494:pharmacology / Q000627:therapeutic use; D060066:Protein Interaction Maps / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D048948:14-3-3 Proteins; D007783:Lactones; D009822:Oils, Volatile; D016271:Proto-Oncogene Proteins c-myc; D012717:Sesquiterpenes; D016159:Tumor Suppressor Protein p53; C083030:dehydrocostus lactone; C002602:costunolide; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt