Rae Colin, Fragkoulis Georgios I, Chalmers Anthony J
Wolfson Wohl Translational Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
Adv Radiat Oncol. 2020 Jun 29;5(5):994-1005. doi: 10.1016/j.adro.2020.06.022. eCollection 2020 Sep-Oct.
Prostate cancers, like many other types of cancer, express elevated levels of fatty acid synthase (FASN) to make more fatty acids, which are required for energy, signaling, and proliferation. Because inhibition of FASN has been shown to sensitize tumors to chemotherapy and radiation, we studied the effect of C75, a radiosensitizing FASN inhibitor, and compared its single agent and radiosensitizing activities in 2 prostate cancer cell lines, PC3 and LNCaP, with alternative FASN inhibitors that have progressed into clinical trials. We also investigated the effect of serum and fatty acid supplementation on responses to FASN inhibitors, probing expression of key proteins related to fatty acid uptake in response to FASN inhibition, irradiation, and serum lipid concentration and how this may be modulated to increase the potency of C75. We demonstrated that C75 was the only FASN inhibitor to sensitize cells to ionizing radiation; no sensitization was apparent with FASN inhibitors TVB-3166 or Orlistat. The prostate cancer cell lines were able to take up fatty acids from the culture medium, and the availability of fatty acids affected sensitivity of these cells to C75 but not the other FASN inhibitors tested. C75 also increased expression of fatty acid transporter proteins FATP1 and CD36. Furthermore, blocking CD36 with antibody increased the sensitivity of cells to C75. We suggest that the potency of C75 is affected by fatty acid availability and that the effectiveness of FASN inhibitors in combination with ionizing radiation can be further enhanced by regulating fatty acid uptake.
与许多其他类型的癌症一样，前列腺癌会高表达脂肪酸合酶（FASN）以生成更多脂肪酸，而能量、信号传导和增殖都需要脂肪酸。由于已证明抑制FASN可使肿瘤对化疗和放疗敏感，我们研究了放射增敏性FASN抑制剂C75的作用，并将其在两种前列腺癌细胞系PC3和LNCaP中的单药活性和放射增敏活性与已进入临床试验的其他FASN抑制剂进行了比较。我们还研究了血清和脂肪酸补充对FASN抑制剂反应的影响，探究了FASN抑制、辐射和血清脂质浓度对脂肪酸摄取相关关键蛋白表达的影响，以及如何调节这些因素以提高C75的效力。我们证明，C75是唯一能使细胞对电离辐射敏感的FASN抑制剂；FASN抑制剂TVB-3166或奥利司他则无明显增敏作用。前列腺癌细胞系能够从培养基中摄取脂肪酸，脂肪酸的可利用性影响这些细胞对C75的敏感性，但不影响所测试的其他FASN抑制剂。C75还增加了脂肪酸转运蛋白FATP1和CD36的表达。此外，用抗体阻断CD36可增加细胞对C75的敏感性。我们认为，C75的效力受脂肪酸可利用性影响，通过调节脂肪酸摄取可进一步增强FASN抑制剂与电离辐射联合使用的效果。
