title: Simvastatin suppresses breast cancer cell proliferation induced by senescent cells.
abstract: Cellular senescence suppresses cancer by preventing the proliferation of damaged cells, but senescent cells can also promote cancer though the pro-inflammatory senescence-associated secretory phenotype (SASP). Simvastatin, an HMG-coA reductase inhibitor, is known to attenuate inflammation and prevent certain cancers. Here, we show that simvastatin decreases the SASP of senescent human fibroblasts by inhibiting protein prenylation, without affecting the senescent growth arrest. The Rho family GTPases Rac1 and Cdc42 were activated in senescent cells, and simvastatin reduced both activities. Further, geranylgeranyl transferase, Rac1 or Cdc42 depletion reduced IL-6 secretion by senescent cells. We also show that simvastatin mitigates the effects of senescent conditioned media on breast cancer cell proliferation and endocrine resistance. Our findings identify a novel activity of simvastatin and mechanism of SASP regulation. They also suggest that senescent cells, which accumulate after radio/chemo therapy, promote endocrine resistance in breast cancer and that simvastatin might suppress this resistance.
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: Santa Rosa Junior College, Santa Rosa, CA 95401, USA.
authors.forename: Harpreet
authors.initials: H
authors.lastname: Uppal
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.|California Pacific Medical Center, Research Institute, San Francisco, CA 94107, USA.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.|Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.affiliation: Buck Institute for Research on Aging, Novato, CA 94945, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Kapahi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D005347:Fibroblasts; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D019821:Simvastatin / Q000494:pharmacology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein