A novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death.
Evasion of death receptor ligand-induced apoptosis is an important contributor to cancer development and progression. Therefore, molecules that restore sensitivity to death receptor stimuli would be important tools to better understand this biological pathway and potential leads for therapeutic adjuncts. Previously, the small-molecule N-[4-chloro-3-(trifluoromethyl)phenyl]-3-oxobutanamide (fasentin) was identified as a chemical sensitizer to the death receptor stimuli FAS and tumor necrosis factor apoptosis-inducing ligand, but its mechanism of action was unknown. Here, we determined that fasentin alters expression of genes associated with nutrient and glucose deprivation. Consistent with this finding, culturing cells in low-glucose medium recapitulated the effects of fasentin and sensitized cells to FAS. Moreover, we showed that fasentin inhibited glucose uptake. Using virtual docking studies with a homology model of the glucose transport protein GLUT1, fasentin interacted with a unique site in the intracellular channel of this protein. Additional chemical studies with other GLUT inhibitors and analogues of fasentin supported a role for partial inhibition of glucose transport as a mechanism to sensitize cells to death receptor stimuli. Thus, fasentin is a novel inhibitor of glucose transport that blocks glucose uptake and highlights a new mechanism to sensitize cells to death ligands.
Wood
Tabitha E
TE
Princess Margaret Hospital, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, Canada.
Dalili
Shadi
S
Simpson
Craig D
CD
Hurren
Rose
R
Mao
Xinliang
X
Saiz
Fernando Suarez
FS
Gronda
Marcela
M
Eberhard
Yanina
Y
Minden
Mark D
MD
Bilan
Philip J
PJ
Klip
Amira
A
Batey
Robert A
RA
Schimmer
Aaron D
AD
D000813:Anilides / Q000138:chemical synthesis / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001665:Binding Sites; D001692:Biological Transport / Q000187:drug effects; D002453:Cell Cycle; D045744:Cell Line, Tumor; D053222:Fas Ligand Protein / Q000378:metabolism; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D008297:Male; D053218:Receptors, Death Domain / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
D000813:Anilides; D000970:Antineoplastic Agents; D053222:Fas Ligand Protein; D051246:Glucose Transport Proteins, Facilitative; D051272:Glucose Transporter Type 1; D053218:Receptors, Death Domain; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; C533793:fasentin; D005947:Glucose