Co-administration of 20(S)-protopanaxatriol (g-PPT) and EGFR-TKI overcomes EGFR-TKI resistance by decreasing SCD1 induced lipid accumulation in non-small cell lung cancer
Co-administration of 20(S)-protopanaxatriol (g-PPT) and EGFR-TKI overcomes EGFR-TKI resistance by decreasing SCD1 induced lipid accumulation in non-small cell lung cancer
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20(S)-原人参三醇 (g-PPT) 和 EGFR-TKI 联合给药可通过减少 SCD1 诱导的非小细胞肺癌脂质积累来克服 EGFR-TKI 耐药性
DOI：
10.1186/s13046-019-1120-4
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发表时间：
2019-03-15
影响因子：
11.3
通讯作者：
Liao, Yongde
中科院分区：
文献类型：
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作者：
Huang, Quanfu;Wang, Qiuguo;Liao, Yongde
具有敏感性表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者可使用EGFR酪氨酸激酶抑制剂（EGFR-TKI）成功治疗;然而，不可避免地会出现耐药。鉴于脂质代谢重编程被广泛认为是癌症的标志，并与EGFR刺激的癌症生长密切相关。EGFR信号通路的激活增加了单不饱和脂肪酸（MUFA）和脂质代谢关键酶硬脂酰辅酶A去饱和酶1（SCD 1）的表达。然而，EGFR-TKI抗性与脂质代谢之间的相关性仍有待确定。在这项研究中，研究了配对的TKI敏感和TKI耐药患者组织和NSCLC细胞系之间脂质合成的差异。采用油酸（OA，一种MUFA，SCD 1酶促产物）模拟高脂代谢环境，检测TKI（吉非替尼和奥希替尼）对EGFR激活突变细胞系细胞毒作用的影响。（20 S）-原人参三醇（g-PPT）是人参皂苷的一种苷元，是一种有效的脂代谢抑制剂，被用来抑制脂质代谢。此外，使用CCK-8测定、蛋白质印迹法、流式细胞术、Edu测定、平板克隆形成测定和免疫荧光法评价细胞毒性作用和信号通路活化的协同作用。此外，使用两种异种移植小鼠模型来验证体外结果。在NSCLC细胞系和患者组织中，吉非替尼耐药细胞的脂滴含量和SCD 1表达均高于吉非替尼敏感细胞。此外，油酸（OA，一种MUFA，SCD 1酶促产物）消除了吉非替尼和奥希替尼在EGFR激活突变细胞系中的细胞毒性作用。g-PPT作为一种有效的脂代谢抑制剂，可显著抑制肺腺癌细胞SCD 1的表达，进而下调细胞内脂滴的含量。吉非替尼和g-PPT联合治疗逆转了对吉非替尼的耐药性，并抑制了p-EGFR和下游信号通路的活化。我们的研究结果揭示了脂质代谢重编程与EGFR-TKI耐药之间的联系，证实了EGFR和异常脂质代谢的联合靶向可能是EGFR-TKI耐药的有希望的治疗方法，并强调了监测肿瘤中脂质积聚以预测耐药性的可能性。
Non-small cell lung cancer (NSCLC) patients with sensitive epidermal growth factor receptor (EGFR) mutations are successfully treated with EGFR tyrosine kinase inhibitors (EGFR-TKIs); however, resistance to treatment inevitably occurs. Given lipid metabolic reprogramming is widely known as a hallmark of cancer and intimately linked with EGFR-stimulated cancer growth. Activation of EGFR signal pathway increased monounsaturated fatty acids (MUFA) and lipid metabolism key enzyme Stearoyl-CoA Desaturase 1 (SCD1) expression. However the correlation between EGFR-TKI resistance and lipid metabolism remains to be determined. In this study the differences in lipid synthesis between paired TKI-sensitive and TKI-resistant patient tissues and NSCLC cell lines were explored. Oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) was used to simulate a high lipid metabolic environment and detected the affection on the cytotoxic effect of TKIs (Gefitinib and osimertinib) in cell lines with EGFR-activating mutations. (20S)-Protopanaxatriol (g-PPT), an aglycone of ginsenosides, has been reported to be an effective lipid metabolism inhibitor, was used to inhibit lipid metabolism. Additionally, synergism in cytotoxic effects and signal pathway activation were evaluated using CCK-8 assays, Western blotting, flow cytometry, Edu assays, plate clone formation assays and immunofluorescence. Furthermore, two xenograft mouse models were used to verify the in vitro results. Gefitinib-resistant cells have higher lipid droplet content and SCD1 expression than Gefitinib-sensitive cells in both NSCLC cell lines and patient tissues. Additionally oleic acid (OA, a kind of MUFA, the SCD1 enzymatic product) abrogates the cytotoxic effect of both Gefitinib and osimertinib in cell lines with EGFR-activating mutations. As a reported effective lipid metabolism inhibitor, g-PPT significantly inhibited the expression of SCD1 in lung adenocarcinoma cells, and then down-regulated the content of intracellular lipid droplets. Combined treatment with Gefitinib and g-PPT reverses the resistance to Gefitinib and inhibits the activation of p-EGFR and the downstream signaling pathways. Our findings uncover a link between lipid metabolic reprogramming and EGFR-TKI resistance, confirmed that combination target both EGFR and abnormal lipid metabolism maybe a promising therapy for EGFR-TKI resistance and highlighting the possibility of monitoring lipid accumulation in tumors for predicting drug resistance.