Cordycepin inhibits lipopolysaccharide-induced cell migration and invasion in human colorectal carcinoma HCT-116 cells through down-regulation of prostaglandin E2 receptor EP4

Prostaglandin E2 (PGE2), a major product of cyclooxygenase-2 (COX-2), plays an important role in the carcinogenesis of many solid tumors, including colorectal cancer. Because PGE2 functions by signaling through PGE2 receptors (EPs), which regulate tumor cell growth, invasion, and migration, there has been a growing amount of interest in the therapeutic potential of targeting EPs. In the present study, we investigated the role of EP4 on the effectiveness of cordycepin in inhibiting the migration and invasion of HCT116 human colorectal carcinoma cells. Our data indicate that cordycepin suppressed lipopolysaccharide (LPS)-enhanced cell migration and invasion through the inactivation of matrix metalloproteinase (MMP)-9 as well as the down-regulation of COX-2 expression and PGE2 production. These events were shown to be associated with the inactivation of EP4 and activation of AMP-activated protein kinase (AMPK). Moreover, the EP4 antagonist AH23848 prevented LPS-induced MMP-9 expression and cell invasion in HCT116 cells. However, the AMPK inhibitor, compound C, as well as AMPK knockdown via siRNA, attenuated the cordycepin-induced inhibition of EP4 expression. Cordycepin treatment also reduced the activation of CREB. These findings indicate that cordycepin suppresses the migration and invasion of HCT116 cells through modulating EP4 expression and the AMPK-CREB signaling pathway. Therefore, cordycepin has the potential to serve as a potent anti-cancer agent in therapeutic strategies against colorectal cancer metastasis.

[1]  J. Boyle,et al.  Celecoxib exerts protective effects in the vascular endothelium via COX-2-independent activation of AMPK-CREB-Nrf2 signalling , 2018, Scientific Reports.

[2]  C. Velasco,et al.  Changes in the levels and phosphorylation status of Akt, AMPK, CREB and FoxO1 in hypothalamus of rainbow trout under conditions of enhanced glucosensing activity , 2017, Journal of Experimental Biology.

[3]  Kyung-Hee Chun,et al.  Kahweol inhibits lipid accumulation and induces Glucose-uptake through activation of AMP-activated protein kinase (AMPK) , 2017, BMB reports.

[4]  Z. Chang,et al.  Cordycepin induces apoptosis in human bladder cancer cells via activation of A3 adenosine receptors , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[5]  T. Tsai,et al.  Metronomic Cordycepin Therapy Prolongs Survival of Oral Cancer-Bearing Mice and Inhibits Epithelial-Mesenchymal Transition , 2017, Molecules.

[6]  Jae-Hong Ko,et al.  Cordycepin induces human lung cancer cell apoptosis by inhibiting nitric oxide mediated ERK/Slug signaling pathway. , 2017, American journal of cancer research.

[7]  Yun Bai,et al.  Cordycepin inhibits chondrocyte hypertrophy of mesenchymal stem cells through PI3K/Bapx1 and Notch signaling pathway , 2016, BMB reports.

[8]  Sang-Min Jeon,et al.  Regulation and function of AMPK in physiology and diseases , 2016, Experimental & Molecular Medicine.

[9]  Robert J. Lee,et al.  Cordycepin, a Natural Antineoplastic Agent, Induces Apoptosis of Breast Cancer Cells via Caspase-dependent Pathways , 2016, Natural product communications.

[10]  M. Young,et al.  Targeting AMPK for cancer prevention and treatment , 2015, Oncotarget.

[11]  Yung-Hyun Choi,et al.  Anti-inflammatory effects of cordycepin in lipopolysaccharide-stimulated RAW 264.7 macrophages through Toll-like receptor 4-mediated suppression of mitogen-activated protein kinases and NF-κB signaling pathways , 2014, Drug design, development and therapy.

[12]  Young Yang,et al.  NDRG2 Controls COX-2/PGE2-Mediated Breast Cancer Cell Migration and Invasion , 2014, Molecules and cells.

[13]  G. Sung,et al.  A Brief Chronicle of the Genus Cordyceps Fr., the Oldest Valid Genus in Cordycipitaceae (Hypocreales, Ascomycota) , 2014, Mycobiology.

[14]  K. Iwatsubo,et al.  The Prostanoid EP4 Receptor and Its Signaling Pathway , 2013, Pharmacological Reviews.

[15]  Meng Ye,et al.  The genus Cordyceps: a chemical and pharmacological review , 2013, The Journal of pharmacy and pharmacology.

[16]  D. Hardie,et al.  Metabolism of inflammation limited by AMPK and pseudo-starvation , 2013, Nature.

[17]  A. Anichini,et al.  AMPK activators inhibit the proliferation of human melanomas bearing the activated MAPK pathway , 2012, Melanoma research.

[18]  R. DuBois,et al.  Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion , 2012, International journal of cell biology.

[19]  S. Narumiya,et al.  International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress , 2011, Pharmacological Reviews.

[20]  R. Shaw,et al.  The AMPK signalling pathway coordinates cell growth, autophagy and metabolism , 2011, Nature Cell Biology.

[21]  Vincent Mirouse,et al.  The LKB1/AMPK polarity pathway , 2011, FEBS letters.

[22]  B. Viollet,et al.  Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy , 2011, Science.

[23]  Wun-Jae Kim,et al.  Cordycepin suppresses TNF‐alpha‐induced invasion, migration and matrix metalloproteinase‐9 expression in human bladder cancer cells , 2010, Phytotherapy research : PTR.

[24]  M. Sakakibara,et al.  Medicinal uses of the mushroom Cordyceps militaris: current state and prospects. , 2010, Fitoterapia.

[25]  B. Viollet,et al.  Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. , 2010, Cell metabolism.

[26]  Y. Daaka,et al.  Prostaglandin E2 Promotes Lung Cancer Cell Migration via EP4-βArrestin1-c-Src Signalsome , 2010, Molecular Cancer Research.

[27]  I. Cho,et al.  H89, an inhibitor of PKA and MSK, inhibits cyclic-AMP response element binding protein-mediated MAPK phosphatase-1 induction by lipopolysaccharide , 2009, Inflammation Research.

[28]  Heather R. Roberts,et al.  The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. , 2009, Carcinogenesis.

[29]  B. Turk,et al.  AMPK phosphorylation of raptor mediates a metabolic checkpoint. , 2008, Molecular cell.

[30]  R. Paterson.  Cordyceps – A traditional Chinese medicine and another fungal therapeutic biofactory? , 2008, Phytochemistry.

[31]  M. Rhee,et al.  Inhibitory effects of cordycepin (3'-deoxyadenosine), a component of Cordyceps militaris, on human platelet aggregation induced by thapsigargin. , 2007, Journal of microbiology and biotechnology.

[32]  M. Lejeune,et al.  Prostaglandin E2 receptor distribution and function in the gastrointestinal tract , 2006, British journal of pharmacology.

[33]  B. Bauer,et al.  The traditional Chinese medicine Cordyceps sinensis and its effects on apoptotic homeostasis. , 2005, Journal of ethnopharmacology.

[34]  K. Metters,et al.  Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype. , 1994, The Journal of biological chemistry.

[35]  Kazuki Nakamura,et al.  Anticancer and antimetastatic effects of cordycepin, an active component of Cordyceps sinensis. , 2015, Journal of pharmacological sciences.

[36]  F. Kambe,et al.  Prostaglandin E2 negatively regulates AMP-activated protein kinase via protein kinase A signaling pathway. , 2009, Prostaglandins & other lipid mediators.