Inhibition of glycolysis enhances cisplatin-induced apoptosis in ovarian cancer cells.
OBJECTIVE
Up-regulation of glycolysis has been demonstrated in multiple tumor types and is believed to originate as an adaptive response to the selective pressure of the tumor microenvironment. We hypothesized that ovarian cancer cells are dependent on the glycolytic pathway for adenosine triphosphate generation and that this phenotype could be exploited for therapeutic intervention.


METHODS
Expression of glucose transporter 1 (Glut1), phosphorylated protein kinase B (pPKB/pAkt), and phosphorylated mammalian target of rapamycin (pmTOR) was assessed in ovarian carcinoma tumors and cell lines. Cells were incubated with 2-deoxyglucose and rapamycin; growth inhibition, viability, and mechanism of cell death were determined.


RESULTS
Ovarian carcinoma cells overexpress Glut1, pAkt, and pmTOR compared with benign ovarian epithelial cells. 2-deoxyglucose and rapamycin markedly enhance apoptotic and nonapoptotic cell death in ovarian cancer cells.


CONCLUSIONS
The glycolytic phenotype of ovarian cancer cells can be targeted for therapeutic intervention. Combined treatment modalities that target multiple cellular pathways hold promise for the treatment of chemoresistant ovarian cancer cells.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA.
Paul
P
Loar
Heather
H
Wahl
Malti
M
Kshirsagar
Gabrielle
G
Gossner
Kent
K
Griffith
J Rebecca
JR
Liu
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000963:Antimetabolites / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
D000903:Antibiotics, Antineoplastic; D000963:Antimetabolites; D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D047908:Intracellular Signaling Peptides and Proteins; C495677:SLC2A1 protein, human; D003847:Deoxyglucose; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D002945:Cisplatin; D020123:Sirolimus