Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy.
Fluvastatin Prevents Lung Adenocarcinoma Bone Metastasis by Triggering Autophagy.
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氟伐他汀通过触发自噬预防肺腺癌骨转移
DOI：
10.1016/j.ebiom.2017.04.017
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发表时间：
2017-05
期刊：
影响因子：
11.1
通讯作者：
Yuan Z
中科院分区：
文献类型：
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作者：
Yang Z;Su Z;DeWitt JP;Xie L;Chen Y;Li X;Han L;Li D;Xia J;Zhang Y;Yang Y;Jin C;Zhang J;Li S;Li K;Zhang Z;Qu X;He Z;Chen Y;Shen Y;Ren M;Yuan Z
骨是肺癌最好的转移部位之一。目前，双磷酸盐和地诺单抗是控制肿瘤相关骨骼相关事件(SRE)的主要药物。然而，双磷酸盐和地诺单抗都显著增加了颌骨骨坏死的风险。他汀类药物是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂，也是最常用的降胆固醇药物，已被报道可抑制肿瘤进展并诱导癌细胞自噬。然而，他汀类药物的作用以及他汀类药物自噬在骨转移中的作用尚不清楚。在这项研究中，我们报道了氟伐他汀有效地预防肺腺癌裸鼠模型的骨转移。我们进一步揭示了氟伐他汀诱导的抗骨转移特性在很大程度上依赖于其诱导肺腺癌细胞自噬的能力。ATG5或ATG7缺失，或3-甲基腺嘌呤(3-MA)或巴菲霉素A1(BafA1)治疗可阻止氟伐他汀抑制骨转移。此外，我们发现氟伐他汀刺激增加了细胞核P53的表达，并且氟伐他汀诱导的自噬和抗骨转移活性主要依赖于P53。氟伐他汀有效预防肺腺癌裸鼠模型骨转移。氟伐他汀诱导的抗骨转移特性在很大程度上依赖于其诱导自噬的能力。氟伐他汀诱导的自噬和抗骨转移活性是由p53介导的。他汀类药物是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶的抑制剂，是使用频率最高、副作用最小的降胆固醇药物。在这项研究中，我们提出了他汀类药物抑制肺腺癌骨转移的新功能，该功能依赖于他汀类药物诱导的自噬。目前，骨转移还没有治愈的方法，目前使用抗骨转移药物的治疗方案都有负面副作用。例如，双磷酸盐或Denosumab治疗减少了与肿瘤相关的骨骼相关事件，但同时增加了颌骨骨坏死的风险。作为一种可能的治疗选择，氟伐他汀有望用于骨转移高危的癌症患者。
Bone is one of the most preferred sites of metastasis in lung cancer. Currently, bisphosphonates and denosumab are major agents for controlling tumor-associated skeletal-related events (SREs). However, both bisphosphonates and denosumab significantly increase the risk for jaw osteonecrosis. Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most frequently prescribed cholesterol-lowering agents, have been reported to inhibit tumor progression and induce autophagy in cancer cells. However, the effects of statin and role of autophagy by statin on bone metastasis are unknown. In this study, we report that fluvastatin effectively prevented lung adenocarcinoma bone metastasis in a nude mouse model. We further reveal that fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy in lung adenocarcinoma cells. Atg5 or Atg7 deletion, or 3-methyadenine (3-MA) or Bafilomycin A1 (Baf A1) treatment prevented the fluvastatin-induced suppression of bone metastasis. Furthermore, we reveal that fluvastatin stimulation increased the nuclear p53 expression, and fluvastatin-induced autophagy and anti-bone metastatic activity were mostly dependent on p53. Fluvastatin effectively prevents lung adenocarcinoma bone metastasis in a nude mouse model. Fluvastatin-induced anti-bone metastatic property was largely dependent on its ability to induce autophagy. Fluvastatin-induced autophagy and anti-bone metastatic activity are mediated by p53. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are most frequently prescribed cholesterol-lowering agent with minimal side effects. In this study, we present a novel function of statins in suppressing lung adenocarcinoma bone metastasis, and this function is dependent on statin-induced autophagy. Currently, there is no cure for bone metastasis, and the current treatment options using anti-bone metastatic agents have negative side effects. For example, bisphosphonates or denosumab treatments reduce tumor-associated skeletal-related events, but simultaneously increase the risk of the osteonecrosis in the jaw. As a possible therapeutic treatment option, fluvastatin is promising to cancer patients with a high risk of bone metastasis.