ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo.
The pathways that allow quiescent disseminated cancer cells to survive during prolonged dormancy periods are unknown. Here, we identify the transcription factor ATF6alpha as a pivotal survival factor for quiescent but not proliferative squamous carcinoma cells. ATF6alpha is essential for the adaptation of dormant cells to chemotherapy, nutritional stress, and, most importantly, the in vivo microenvironment. Mechanism analysis showed that MKK6 and p38alpha/beta contribute to regulating nuclear translocation and transcriptional activation of ATF6alpha in dormant cancer cells. Downstream, ATF6alpha induces survival through the up-regulation of Rheb and activation of mTOR signaling independent of Akt. Down-regulation of ATF6alpha or Rheb reverted dormant tumor cell resistance to rapamycin and induced pronounced killing only of dormant cancer cells in vivo. Knocking down ATF6alpha also prolonged the survival of nude mice bearing dormant tumor cells. Targeting survival signaling by the ATF6alpha-Rheb-mTOR pathway in dormant tumor cells may favor the eradication of residual disease during dormancy periods.
Schewe
Denis M
DM
Department of Biomedical Sciences, School of Public Health and Center for Excellence in Cancer Genomics, University at Albany, State University of New York, One Discovery Drive, Rensselaer, NY 12144, USA.
Aguirre-Ghiso
Julio A
JA
D051702:Activating Transcription Factor 6 / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011494:Protein Kinases / Q000378:metabolism*; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D009479:Neuropeptides; C490211:RHEB protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020559:Monomeric GTP-Binding Proteins