An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer Journal Article
| Authors: | Chen, M.; Zhang, J.; Sampieri, K.; Clohessy, J. G.; Mendez, L.; Gonzalez-Billalabeitia, E.; Liu, X. S.; Lee, Y. R.; Fung, J.; Katon, J. M.; Menon, A. V.; Webster, K. A.; Ng, C.; Palumbieri, M. D.; Diolombi, M. S.; Breitkopf, S. B.; Teruya-Feldstein, J.; Signoretti, S.; Bronson, R. T.; Asara, J. M.; Castillo-Martin, M.; Cordon-Cardo, C.; Pandolfi, P. P. |
| Article Title: | An aberrant SREBP-dependent lipogenic program promotes metastatic prostate cancer |
| Abstract: | Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten-null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten-null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis. © 2018 The Author(s). |
| Keywords: | epidermal growth factor; mitogen activated protein kinase; s6 kinase; controlled study; protein expression; unclassified drug; major clinical study; clinical feature; nonhuman; lymph node metastasis; antineoplastic agent; mouse; animal tissue; protein targeting; animal experiment; animal model; in vivo study; enzyme activation; distant metastasis; prostate cancer; cancer inhibition; lung metastasis; prostaglandin; mammalian target of rapamycin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; triacylglycerol; phosphatidylethanolamine; tumor growth; arachidonic acid; lipogenesis; protein inhibitor; phosphatidylcholine; knockout mouse; lipid analysis; sphingomyelin; promyelocytic leukemia protein; metastasis inhibition; oleic acid; phosphatidylserine; palmitic acid; lysophosphatidylcholine; phosphatidylinositol; sterol regulatory element binding protein; stearic acid; lipidomics; human; male; priority journal; article; cardiolipin; phosphatidylglycerol; fatostatin |
| Journal Title: | Nature Genetics |
| Volume: | 50 |
| Issue: | 2 |
| ISSN: | 1061-4036 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-02-01 |
| Start Page: | 206 |
| End Page: | 218 |
| Language: | English |
| DOI: | 10.1038/s41588-017-0027-2 |
| PROVIDER: | scopus |
| PUBMED: | 29335545 |
| PMCID: | PMC6714980 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2018 -- Source: Scopus |
