Proton pump inhibitors suppress DNA damage repair and sensitize treatment resistance in breast cancer by targeting fatty acid synthase.
Proton pump inhibitors suppress DNA damage repair and sensitize treatment resistance in breast cancer by targeting fatty acid synthase.
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DOI：
10.1016/j.canlet.2021.03.026
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发表时间：
2021-07-01
期刊：
影响因子：
9.7
通讯作者：
Liu JY
中科院分区：
文献类型：
--
作者：
Wang CJ;Li D;Danielson JA;Zhang EH;Dong Z;Miller KD;Li L;Zhang JT;Liu JY
人脂肪酸合成酶（Human fatty acid synthase，FATCH）是负责脂质从头合成的唯一胞质酶。脂肪酸对于癌细胞存活是必需的，并且通过上调DNA损伤修复而有助于药物和辐射抗性，但对于大多数非脂肪生成组织来说不是必需的。因此，Festival是药物发现的有吸引力的靶标。然而，尽管数十年来一直致力于靶向Festival，但由于药代动力学或毒性较差，尚未批准Festival抑制剂。在这里，我们表明，FDA批准的质子泵抑制剂（PPI）有效地抑制FXR和抑制乳腺癌细胞的存活。PPI抑制FXR通过减少FASN介导的PARP 1表达，导致DNA损伤的非同源末端连接修复受到抑制，从而导致氧化性DNA损伤引起的细胞凋亡以及细胞对多柔比星和电离辐射的耐受性敏化。对6,754名乳腺癌患者的电子病历进行挖掘，结果显示，PPI的使用显著提高了这些患者的总生存率，并降低了疾病复发率。因此，PPI可以通过靶向FXR和克服耐药性和辐射抗性，重新用作乳腺癌治疗的抗癌药物。
Human fatty acid synthase (FASN) is the sole cytosolic enzyme responsible for de novo lipid synthesis. FASN is essential for cancer cell survival and contributes to drug and radiation resistance by up-regulating DNA damage repair but not required for most non-lipogenic tissues. Thus, FASN is an attractive target for drug discovery. However, despite decades of effort in targeting FASN, no FASN inhibitors have been approved due to poor pharmacokinetics or toxicities. Here, we show that the FDA-approved proton pump inhibitors (PPIs) effectively inhibit FASN and suppress breast cancer cell survival. PPI inhibition of FASN leads to suppression of non-homologous end joining repair of DNA damages by reducing FASN-mediated PARP1 expression, resulting in apoptosis from oxidative DNA damages and sensitization of cellular resistance to doxorubicin and ionizing radiation. Mining electronic medical records of 6,754 breast cancer patients showed that PPI usage significantly increased overall survival and reduced disease recurrence of these patients. Hence, PPIs may be repurposed as anticancer drugs for breast cancer treatments by targeting FASN and to overcome drug and radiation resistance.
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影响因子：
8.8
作者：
Mashima, T.;Seimiya, H.;Tsuruo, T.
通讯作者：
Tsuruo, T.
影响因子：
4.8
作者：
Knowles, LM;Axelrod, F;Smith, JW
通讯作者：
Smith, JW
DOI：
10.1073/pnas.91.14.6379
发表时间：
1994-07-05
影响因子：
11.1
作者：
KUHAJDA, FP;JENNER, K;PASTERNACK, GR
通讯作者：
PASTERNACK, GR
影响因子：
10.3
作者：
Migita, Toshiro;Ruiz, Stacey;Loda, Massimo
通讯作者：
Loda, Massimo
DOI：
10.2217/fon.10.11
发表时间：
2010-04
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Flavin R;Peluso S;Nguyen PL;Loda M
通讯作者：
Loda M