Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model
Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model
复制标题
在原位小鼠模型中，口服重组蛋氨酸酶与激动剂替加妥珠单抗联合使用可增加 TRAIL 受体 2 表达以消退胰腺癌
DOI：
10.1016/j.canlet.2020.07.034
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Hoffman RM
中科院分区：
文献类型：
--
作者：
Yamamoto J;Miyake K;Han Q;Tan Y;Inubushi S;Sugisawa N;Higuchi T;Tashiro Y;Nishino H;Homma Y;Matsuyama R;Chawla SP;Bouvet M;Singh SR;Endo I;Hoffman RM
Methionine addiction is a fundamental and general hallmark of cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted cancer cells increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluatedin vitro. An orthotopic pancreatic cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced apoptosis, by increasing TRAIL-R2 expression in pancreatic cancer cellsin vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic cancer.
