Simvastatin suppresses breast cancer cell proliferation induced by senescent cells.
Simvastatin suppresses breast cancer cell proliferation induced by senescent cells.
复制标题
DOI：
10.1038/srep17895
复制
发表时间：
2015-12-14
影响因子：
4.6
通讯作者：
Kapahi P
中科院分区：
文献类型：
--
作者：
Liu S;Uppal H;Demaria M;Desprez PY;Campisi J;Kapahi P
细胞衰老通过阻止受损细胞的增殖来抑制癌症，但衰老细胞也可以通过促炎衰老相关分泌表型（SASP）促进癌症。辛伐他汀是一种HMG-CoA还原酶抑制剂，已知可减轻炎症并预防某些癌症。在这里，我们发现辛伐他汀通过抑制蛋白质异戊烯化来降低衰老的人成纤维细胞的SASP，而不影响衰老的生长停滞。Rho家族GTP酶Rac 1和Cdc 42在衰老细胞中被激活，辛伐他汀降低了这两种活性。此外，香叶基香叶基转移酶，Rac 1或Cdc 42耗竭减少衰老细胞的IL-6分泌。我们还表明，辛伐他汀减轻衰老条件培养基对乳腺癌细胞增殖和内分泌抵抗的影响。我们的研究结果确定了辛伐他汀的新活性和SASP调节机制。他们还认为，衰老细胞在放疗/化疗后积累，促进乳腺癌的内分泌抵抗，辛伐他汀可能抑制这种抵抗。
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.