Xyloketal B suppresses glioblastoma cell proliferation and migration in vitro through inhibiting TRPM7-regulated PI3K/Akt and MEK/ERK signaling pathways.
Glioblastoma, the most common and aggressive type of brain tumors, has devastatingly proliferative and invasive characteristics. The need for finding a novel and specific drug target is urgent as the current approaches have limited therapeutic effects in treating glioblastoma. Xyloketal B is a marine compound obtained from mangrove fungus Xylaria sp. (No. 2508) from the South China Sea, and has displayed antioxidant activity and protective effects on endothelial and neuronal oxidative injuries. In this study, we used a glioblastoma U251 cell line to (1) explore the effects of xyloketal B on cell viability, proliferation, and migration; and (2) investigate the underlying molecular mechanisms and signaling pathways. MTT assay, colony formation, wound healing, western blot, and patch clamp techniques were employed. We found that xyloketal B reduced cell viability, proliferation, and migration of U251 cells. In addition, xyloketal B decreased p-Akt and p-ERK1/2 protein expressions. Furthermore, xyloketal B blocked TRPM7 currents in HEK-293 cells overexpressing TRPM7. These effects were confirmed by using a TRPM7 inhibitor, carvacrol, in a parallel experiment. Our findings indicate that TRPM7-regulated PI3K/Akt and MEK/ERK signaling is involved in anti-proliferation and migration effects of xyloketal B on U251 cells, providing in vitro evidence for the marine compound xyloketal B to be a potential drug for treating glioblastoma.
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. james.rutka@sickkids.ca.|Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. james.rutka@sickkids.ca.|Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. james.rutka@sickkids.ca.
Wen-Liang
WL
Chen
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. e.turlova@mail.utoronto.ca.
Ekaterina
E
Turlova
Faculty of Applied Science & Engineering, University of Toronto, Toronto, ON M5S 1A4, Canada. christopher.sun@mail.utoronto.ca.
Christopher L F
CL
Sun
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. jsk.kim@mail.utoronto.ca.
Ji-Sun
JS
Kim
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. sammen.huang@mail.utoronto.ca.
Sammen
S
Huang
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. james.rutka@sickkids.ca.|Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. james.rutka@sickkids.ca.
Xiao
X
Zhong
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. guanyy@mail.sysu.edu.cn.
Yong-Yuan
YY
Guan
Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. wangglei@mail.sysu.edu.cn.|Key Laboratory of Functional Molecules from Oceanic Microorganisms, Department of Education of Guangdong Province, Sun Yat-sen University, Guangzhou 510080, China. wangglei@mail.sysu.edu.cn.
Guan-Lei
GL
Wang
Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. james.rutka@sickkids.ca.
James T
JT
Rutka
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. zp.feng@utoronto.ca.
Zhong-Ping
ZP
Feng
Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. hss.sun@utoronto.ca.|Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. hss.sun@utoronto.ca.|Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. hss.sun@utoronto.ca.|Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada. hss.sun@utoronto.ca.
Hong-Shuo
HS
Sun
D000970:Antineoplastic Agents / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000737:chemistry / Q000254:growth & development; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002681:China; D015536:Down-Regulation / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010140:Pacific Ocean; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053833:Wetlands; D013098:Xylariales / Q000737:chemistry / Q000254:growth & development
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011714:Pyrans; D050053:TRPM Cation Channels; C515343:xyloketal B; D058539:Phosphatidylinositol 3-Kinase; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C486583:TRPM7 protein, human