A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.
"Oncogene addiction" describes an unexplained dependency of cancer cells on a particular cellular pathway for survival or proliferation. We report that differential attenuation rates of prosurvival and proapoptotic signals in oncogene-dependent cells contribute to cell death following oncogene inactivation. Src-, BCR-ABL-, and EGF receptor-dependent cells exhibit a similar profile of signal attenuation following oncogene inactivation characterized by rapid diminution of phospho-ERK, -Akt, and -STAT3/5, and a delayed accumulation of the proapoptotic effector phospho-p38 MAPK. These findings implicate a transient imbalance in survival and apoptotic oncogenic outputs in the apoptotic response to oncogene inactivation. Moreover, these observations implicate a common profile of signal attenuation for multiple oncogenes and suggest that "addiction" associated with apoptosis reflects an active rather than a passive process.
Sharma
Sreenath V
SV
Massachusetts General Hospital Cancer Center and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Gajowniczek
Patrycja
P
Way
Inna P
IP
Lee
Diana Y
DY
Jiang
Jane
J
Yuza
Yuki
Y
Classon
Marie
M
Haber
Daniel A
DA
Settleman
Jeffrey
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D016313:Genes, abl; D006801:Humans; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013696:Temperature; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D019061:src-Family Kinases; D010744:Phosphoric Monoester Hydrolases