MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy.
Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy.
Balakumaran
Bala S
BS
Duke Institute for Genome Sciences and Policy and Duke Comprehensive Cancer Center, Duke University, NC 27710, USA.
Porrello
Alessandro
A
Hsu
David S
DS
Glover
Wayne
W
Foye
Adam
A
Leung
Janet Y
JY
Sullivan
Beth A
BA
Hahn
William C
WC
Loda
Massimo
M
Febbo
Phillip G
PG
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D024721:E-Box Elements; D039561:Eukaryotic Initiation Factor-4E / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D016259:Genes, myc; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D014415:Tunicamycin / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D039561:Eukaryotic Initiation Factor-4E; D016271:Proto-Oncogene Proteins c-myc; D014415:Tunicamycin; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus