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Endogenous arginase 2 as a potential biomarker for PEGylated arginase 1 treatment in xenograft models of squamous cell lung carcinoma.
Oncogenesis ( IF 5.9 ) Pub Date : 2019-02-26 , DOI: 10.1038/s41389-019-0128-0 Sze-Kwan Lam 1 , Sheng Yan 1 , Shi Xu 1 , Kin-Pong U 2 , Paul Ning-Man Cheng 3 , James Chung-Man Ho 1
Oncogenesis ( IF 5.9 ) Pub Date : 2019-02-26 , DOI: 10.1038/s41389-019-0128-0 Sze-Kwan Lam 1 , Sheng Yan 1 , Shi Xu 1 , Kin-Pong U 2 , Paul Ning-Man Cheng 3 , James Chung-Man Ho 1
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Depletion of arginine induced by PEGylated arginase 1 (ARG1) (BCT-100) has shown anticancer effects in arginine auxotrophic cancers that lack argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). High levels of endogenous arginase 2 (ARG2) have been previously reported in human lung cancers. Although a high-ARG2 level neither causes immunosuppression nor affects disease progression, it may theoretically affect the efficacy of PEGylated ARG1 treatment. ARG2 was shown to be highly expressed in H520 squamous cell lung carcinoma (lung SCC) xenografts but undetectable in SK-MES-1 and SW900 lung SCC xenografts. We propose that high-endogenous expression of ARG2 could impede the anti-tumor effect of PEGylated ARG1 in lung SCC. The in vivo effect of PEGylated ARG1 was investigated using three xenograft models of lung SCC. PEGylated ARG1 (60 mg/kg) suppressed tumor growth in SK-MES-1 and SW900 but not H520 xenografts. ASS1 was expressed in SK-MES-1 and SW900 xenografts while OTC expression remained low in all xenografts. A high-endogenous ARG2 level was detected only in H520 xenografts. Serum arginine level was decreased significantly by PEGylated ARG1 in all xenografts. Nonetheless intratumoral arginine level was decreased by PEGylated ARG1 in SK-MES-1 and SW900, not H520 xenografts. In SK-MES-1 xenografts, PEGylated ARG1 treatment induced G1 arrest, downregulation of Ki67 and Mcl-1 and activation of apoptosis. In SW900 xenografts, upregulation of Bim and activation of apoptosis were observed upon PEGylated ARG1 treatment. Silencing of ARG2 re-sensitized the H520 xenografts to PEGylated ARG1 treatment, partially mediated through arginine depletion via G1 arrest and apoptosis. PEGylated ARG1 treatment (BCT-100) was effective in lung SCC xenografts with low-endogenous levels of ASS1/OTC and ARG2. High-endogenous ARG2 expression may cause resistance to PEGylated ARG1 treatment in lung SCC xenografts. ARG2 may serve as a third predictive biomarker in PEGylated ARG1 treatment in lung SCC.
中文翻译：
内源性精氨酸酶2作为鳞状细胞肺癌异种移植模型中PEG化精氨酸酶1治疗的潜在生物标志物。
PEG化精氨酸酶1（ARG1）（BCT-100）诱导的精氨酸耗竭已显示出在缺乏精氨琥珀酸合成酶（ASS1）和鸟氨酸转氨甲酰酶（OTC）的精氨酸营养缺陷型癌症中的抗癌作用。先前已在人类肺癌中报道了高水平的内源性精氨酸酶2（ARG2）。尽管高ARG2水平既不会导致免疫抑制也不会影响疾病进展，但从理论上讲，它可能会影响PEG化ARG1治疗的疗效。已显示ARG2在H520鳞状细胞肺癌（肺SCC）异种移植物中高表达，但在SK-MES-1和SW900肺SCC异种移植物中未检测到。我们提出，ARG2的高内源性表达可能会阻止聚乙二醇化的ARG1在肺SCC中的抗肿瘤作用。使用三种肺SCC异种移植模型研究了PEG化ARG1的体内作用。聚乙二醇化的ARG1（60 mg / kg）抑制SK-MES-1和SW900中的肿瘤生长，但不抑制H520异种移植物中的肿瘤生长。ASS1在SK-MES-1和SW900异种移植物中表达，而OTC表达在所有异种移植物中均保持较低水平。仅在H520异种移植物中检测到高内源性ARG2水平。在所有异种移植物中，聚乙二醇化的ARG1均可显着降低血清精氨酸水平。然而，在SK-MES-1和SW900而不是H520异种移植物中，PEG化的ARG1降低了肿瘤内精氨酸水平。在SK-MES-1异种移植物中，PEG化ARG1处理可诱导G1阻滞，Ki67和Mcl-1的下调以及细胞凋亡的激活。在SW900异种移植物中，在PEG化ARG1处理后观察到Bim的上调和细胞凋亡的激活。沉默ARG2使H520异种移植物对PEG化ARG1处理重新敏感，部分通过G1阻滞和凋亡引起的精氨酸消耗而介导。PEG化ARG1处理（BCT-100）在低内源性ASS1 / OTC和ARG2水平的肺SCC异种移植物中有效。高内源性ARG2表达可能导致对肺SCC异种移植物中的PEG化ARG1处理产生抗药性。ARG2可能在肺SCC的PEG化ARG1治疗中作为第三个预测性生物标志物。
更新日期：2019-11-18
中文翻译：
内源性精氨酸酶2作为鳞状细胞肺癌异种移植模型中PEG化精氨酸酶1治疗的潜在生物标志物。
PEG化精氨酸酶1（ARG1）（BCT-100）诱导的精氨酸耗竭已显示出在缺乏精氨琥珀酸合成酶（ASS1）和鸟氨酸转氨甲酰酶（OTC）的精氨酸营养缺陷型癌症中的抗癌作用。先前已在人类肺癌中报道了高水平的内源性精氨酸酶2（ARG2）。尽管高ARG2水平既不会导致免疫抑制也不会影响疾病进展，但从理论上讲，它可能会影响PEG化ARG1治疗的疗效。已显示ARG2在H520鳞状细胞肺癌（肺SCC）异种移植物中高表达，但在SK-MES-1和SW900肺SCC异种移植物中未检测到。我们提出，ARG2的高内源性表达可能会阻止聚乙二醇化的ARG1在肺SCC中的抗肿瘤作用。使用三种肺SCC异种移植模型研究了PEG化ARG1的体内作用。聚乙二醇化的ARG1（60 mg / kg）抑制SK-MES-1和SW900中的肿瘤生长，但不抑制H520异种移植物中的肿瘤生长。ASS1在SK-MES-1和SW900异种移植物中表达，而OTC表达在所有异种移植物中均保持较低水平。仅在H520异种移植物中检测到高内源性ARG2水平。在所有异种移植物中，聚乙二醇化的ARG1均可显着降低血清精氨酸水平。然而，在SK-MES-1和SW900而不是H520异种移植物中，PEG化的ARG1降低了肿瘤内精氨酸水平。在SK-MES-1异种移植物中，PEG化ARG1处理可诱导G1阻滞，Ki67和Mcl-1的下调以及细胞凋亡的激活。在SW900异种移植物中，在PEG化ARG1处理后观察到Bim的上调和细胞凋亡的激活。沉默ARG2使H520异种移植物对PEG化ARG1处理重新敏感，部分通过G1阻滞和凋亡引起的精氨酸消耗而介导。PEG化ARG1处理（BCT-100）在低内源性ASS1 / OTC和ARG2水平的肺SCC异种移植物中有效。高内源性ARG2表达可能导致对肺SCC异种移植物中的PEG化ARG1处理产生抗药性。ARG2可能在肺SCC的PEG化ARG1治疗中作为第三个预测性生物标志物。
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