title: Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells.
abstract: The Warburg effect is an important characteristic of tumor cells, making it an attractive therapeutic target. Current anticancer drug development strategies predominantly focus on inhibitors of the specific molecular effectors involved in tumor cell proliferation. These drugs or natural compounds, many of which target the Warburg effect and the underlying mechanisms, still need to be characterized. To elucidate the anticancer effects of a natural diterpenoid, oridonin, we first demonstrated the anticancer activity of oridonin both in vitro and in vivo in colorectal cancer (CRC) cells. Then miRNA profiling of SW480 cells revealed those intracellular signaling related to energy supply was affected by oridonin, suggesting that glucose metabolism is a potential target for CRC therapy. Moreover, our results indicated that oridonin induced metabolic imbalances by significantly inhibiting glucose uptake and reducing lactate export through significantly downregulating the protein levels of GLUT1 and MCT1 in vitro and vivo. However, the ATP level in oridonin-treated CRC cells was not decreased when oridonin blocked the glucose supply, indicating that oridonin induced autophagy process, an important ATP source in cancer cells. The observation was then supported by the results of LC3-II detection and transmission electron microscopy analysis, which confirmed the presence of autophagy. Furthermore, p-AMPK was rapidly deactivated following oridonin treatment, resulting in downregulation of GLUT1 and induction of autophagy in the cancer cells. Thus our finding helped to clarify the anticancer mechanisms of oridonin and suggested it could be applied as a glucose metabolism-targeting agent for cancer treatment.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Fuhua
authors.initials: F
authors.lastname: Xie
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Zirui
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Wenli
authors.initials: W
authors.lastname: Xu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yang
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Hongwangwang
authors.initials: H
authors.lastname: Li
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
authors.forename: Liang-Hu
authors.initials: LH
authors.lastname: Qu
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045786:Diterpenes, Kaurane / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D045786:Diterpenes, Kaurane; D051272:Glucose Transporter Type 1; D035683:MicroRNAs; D015513:Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C011959:oridonin; D000255:Adenosine Triphosphate; D005947:Glucose