title: Metabolic reprogramming and AMPKα1 pathway activation by caulerpin in colorectal cancer cells.
abstract: Caulerpin, a secondary metabolite from the marine invasive green algae Caulerpa cylindracea is known to induce mitochondrial dysfunctions. In this study, the anticancer property of caulerpin was assessed in a panel of colorectal cancer cell lines. We demonstrated that caulerpin inhibited oxidative phosphorylation (OXPHOS) and facilitated an early intervention of the mitochondrial function, via inhibiting mitochondrial complex I, accompanied by the dissipation of mitochondrial membrane potential and a surge of reactive oxygen species (ROS) generation. Moreover, in response to the increment in AMP/ATP ratio, the energy sensor AMP-activated protein kinase (AMPK) was activated by caulerpin treatment in a calcium/calmodulin-dependent protein kinase 2 (CaMKK2)‑dependent manner. Distinguished effect on glycolysis was observed at different time-points after caulerpin treatment. Glycolysis was enhanced after a short time treatment with caulerpin, associated with upregulation of glucose transporter 1 (GLUT1), hexokinase II (HKII) and 6-phosphofructo-2-kinase (PFKFB3) protein expressions. However, long-term activation of AMPK by caulerpin damaged the glycolysis and glucose metabolism in colorectal cells, finally causing cell death. The persistent effect of caulerpin was mediated by AMPKα1, rather than AMPKα2, to abolish cell viability through hindering mTORC1-4E-BP1 axis. Moreover, caulerpin synergized with the glycolytic inhibitor 3BP in inhibiting cellular proliferation both in vitro and in vivo. Our findings on the previously uncharacterized anticancer effects of caulerpin may provide potential therapeutic approaches targeting the colorectal carcinoma metabolism.
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Nutriology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Huiqin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Dong
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Zhonglei
authors.initials: Z
authors.lastname: Shen
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Zhenfang
authors.initials: Z
authors.lastname: Kong
authors.affiliation: Department of Anus and Intestine Surgery, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Dai
authors.affiliation: Department of Nutriology, Ningbo No. 2 Hospital, Ningbo, Zhejiang 315010, P.R. China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Xu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D065150:Cellular Reprogramming / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage*; D000076222:Mechanistic Target of Rapamycin Complex 1; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics; D046912:Multiprotein Complexes / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; C000392:caulerpin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human