Manumycin inhibits STAT3, telomerase activity, and growth of glioma cells by elevating intracellular reactive oxygen species generation.
The poor prognosis of glioblastoma multiforme and lack of effective therapy have necessitated the identification of new treatment strategies. We have previously reported that elevation of oxidative stress induces apoptosis of glioma cells. Because the farnesyltransferase inhibitor manumycin is known to induce reactive oxygen species (ROS) generation, we evaluated the effects of manumycin on glioma cells. Manumycin induced glioma cell apoptosis by elevating ROS generation. Treatment with the ROS inhibitor N-acetylcysteine blocked manumycin-induced apoptosis, caspase-3 activity, and PARP expression, indicating the involvement of increased ROS in the proapoptotic activity of manumycin. This heightened ROS level was accompanied by a concurrent decrease in antioxidants such as superoxide dismutase (SOD-1) and thioredoxin (TRX-1). SOD-1 overexpression protects glioma cells from manumycin-induced apoptosis. In addition, small interfering RNA-mediated knockdown of SOD-1 and TRX-1 expression also increased ROS generation and sensitivity of glioma cells to manumycin-induced cell death. Interestingly, suppressing ROS generation prevented manumycin-induced Ras inhibition. This study reports for the first time that Ras inhibition by manumycin is due to heightened ROS levels. We also report for the first time that manumycin inhibits the phosphorylation of signal transducer and activator of transcription 3 and telomerase activity in a ROS-dependent manner, which plays a crucial role in glioma resistance to apoptosis. In addition manumycin (i) induced the DNA-damage repair response, (ii) affected cell-cycle-regulatory molecules, and (iii) impaired the colony-forming ability of glioma cells in a ROS-dependent manner.
Dixit
Deobrat
D
National Brain Research Centre, Manesar, Haryana 122050, India.
Sharma
Vivek
V
Ghosh
Sadashib
S
Koul
Nitin
N
Mishra
Prakash Kumar
PK
Sen
Ellora
E
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D005910:Glioma / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D006801:Humans; D018384:Oxidative Stress; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000494:pharmacology / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D019098:Telomerase / Q000378:metabolism*; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism
D011090:Polyenes; D053284:Polyunsaturated Alkamides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000606290:SOD1 protein, human; D050796:STAT3 Transcription Factor; C491203:TXN protein, human; D013879:Thioredoxins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D011065:Poly(ADP-ribose) Polymerases; D051231:Farnesyltranstransferase; D019098:Telomerase; D053148:Caspase 3; D016283:Proto-Oncogene Proteins p21(ras); C054474:manumycin; D000111:Acetylcysteine