Scoles Daniel R, Xu Xuan, Wang Haimei, Tran Hang, Taylor-Harding Barbie, Li Andrew, Karlan Beth Y
Women's Cancer Research Institute and Division of Gynecologic Oncology, CSMC Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, USA.
Gynecol Oncol. 2010 Jan;116(1):109-16. doi: 10.1016/j.ygyno.2009.09.034. Epub 2009 Oct 24.
We previously observed an association between ovarian cancer outcome and statin use and hypothesized lipoproteins have direct effects on ovarian cancer proliferation. Here we investigate the direct effects of low density lipoprotein (LDL) and oxidized LDL (oxLDL) on proliferation and the inhibitory effects of fluvastatin and a liver X receptor (LXR) agonist.
The effects of LDL, oxLDL, the LXR agonist TO901317, fluvastatin and cisplatin on cellular proliferation were determined using MTT assays. LXR pathway proteins were assayed by immunoblotting. Cytokine expression was determined by antibody array.
Concentrations of oxLDL as small as 0.1 microg/ml stimulated CAOV3 and SKOV3 proliferation, while LDL had no effect. TO901317 inhibited the proliferation of CAOV3, OVCAR3 and SKOV3 cells stimulated by oxLDL. Fluvastatin inhibited oxLDL mediated proliferation of CAOV3 and SKOV3. Cardiotrophin 1 (CT-1) was mitogenic to CAOV3 and SKOV3, was induced by oxLDL, and was reversed by TO901317. OxLDL increased cisplatin IC50s by 3.8 microM and > 60 microM for CAOV3 and SKOV3 cells, respectively. The LXR pathway proteins CD36, LXR, and ABCA1 were expressed in eight ovarian carcinoma cell lines (A2780, CAOV3, CP70, CSOC882, ES2, OVCAR3, SKOV3).
OxLDL reduced ovarian carcinoma cell chemosensitivity and stimulated proliferation. These effects were reversed by LXR agonist or fluvastatin. The LXR agonist also inhibited expression of the ovarian cancer mitogen CT-1. These observations suggest a biologic mechanism for our clinical finding that ovarian cancer survival is associated with statin use. Targeting LXR and statin use may have a therapeutic role in ovarian cancer.
我们之前观察到卵巢癌预后与他汀类药物使用之间存在关联，并推测脂蛋白对卵巢癌增殖有直接影响。在此，我们研究低密度脂蛋白（LDL）和氧化型低密度脂蛋白（oxLDL）对增殖的直接影响以及氟伐他汀和肝脏X受体（LXR）激动剂的抑制作用。
使用MTT法测定LDL、oxLDL、LXR激动剂TO901317、氟伐他汀和顺铂对细胞增殖的影响。通过免疫印迹法检测LXR途径蛋白。通过抗体芯片测定细胞因子表达。
低至0.1微克/毫升的oxLDL浓度即可刺激CAOV3和SKOV3细胞增殖，而LDL无此作用。TO901317可抑制oxLDL刺激的CAOV3、OVCAR3和SKOV3细胞增殖。氟伐他汀可抑制oxLDL介导的CAOV3和SKOV3细胞增殖。心肌营养素1（CT-1）对CAOV3和SKOV3细胞有促有丝分裂作用，可被oxLDL诱导，并被TO901317逆转。oxLDL分别使CAOV3和SKOV3细胞的顺铂IC50增加3.8微摩尔和>60微摩尔。LXR途径蛋白CD36、LXR和ABCA1在八种卵巢癌细胞系（A2780、CAOV3、CP70、CSOC882、ES2、OVCAR3、SKOV3）中表达。
oxLDL降低了卵巢癌细胞的化疗敏感性并刺激增殖。这些作用可被LXR激动剂或氟伐他汀逆转。LXR激动剂还可抑制卵巢癌促有丝分裂原CT-1的表达。这些观察结果提示了我们临床发现卵巢癌生存与他汀类药物使用相关的生物学机制。靶向LXR和使用他汀类药物可能在卵巢癌治疗中发挥作用。
