title: Carnosic acid induces autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells.
abstract: The therapeutic goal of cancer treatment is now geared towards triggering tumour-selective cell death with autophagic cell death being required for the chemotherapy of apoptosis-resistant cancer. In this study, Carnosic acid (CA), a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), significantly induced autophagic cell death in HepG2 cells. Ca treatment caused the formation of autophagic vacuoles produced an increasing ratio of LC3-II to LC3-I in a time- and dose-dependent manner but had no effect on the levels of autophagy-related protein ATG6 and ATG13 expression. Autophagy inhibitors, 3-methyladenine (3-MA), chloroquine and bafilomycin A1, or ATG genes silencing in HepG2 cells significantly inhibited CA-induced autophagic cell death. The CA treatment decreased the levels of phosphorylated Akt and mTOR without any effects on PI3K or PTEN. Most importantly, overexpression of Akt and knockdown of PTEN attenuated autophagy induction in CA-treated cells. Taken together, our results indicated that CA induced autophagic cell death through inhibition of the Akt/mTOR pathway in human hepatoma cells. These findings suggest that CA has a great potential for the treatment of hepatoma via autophagic induction.
authors.affiliation: Department of integrated traditional Chinese and western medicine, Affiliated cancer hospital of Zhengzhou University, Zhengzhou, Henan, 450008, China.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Gao
authors.forename: Huaimin
authors.initials: H
authors.lastname: Liu
authors.forename: Yamin
authors.initials: Y
authors.lastname: Yao
authors.forename: Liang
authors.initials: L
authors.lastname: Geng
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Lifeng
authors.initials: L
authors.lastname: Jiang
authors.forename: Bian
authors.initials: B
authors.lastname: Shi
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
mesh_terms: D045784:Abietanes / Q000009:adverse effects*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D049109:Cell Proliferation; D002738:Chloroquine / Q000494:pharmacology; D020868:Gene Silencing; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D018942:Macrolides / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000009:adverse effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D045784:Abietanes; D000225:Adenine; D002738:Chloroquine; D018942:Macrolides; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010936:Plant Extracts; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C025946:3-methyladenine; C040929:bafilomycin A1; C546842:MTOR protein, human; C494929:PTEN protein, human; C018381:salvin
keywords: ATG; Akt; autophagy; carnosic acid; hepatoma; proliferation