Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.
Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.
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DOI：
10.3389/fonc.2021.758549
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发表时间：
2021
影响因子：
4.7
通讯作者：
Itoh Y
中科院分区：
文献类型：
--
作者：
Okuda K;Umemura A;Kataoka S;Yano K;Takahashi A;Okishio S;Taketani H;Seko Y;Nishikawa T;Yamaguchi K;Moriguchi M;Nakagawa H;Liu Y;Mitsumoto Y;Kanbara Y;Shima T;Okanoue T;Itoh Y
肝细胞癌（HCC）是最常见的原发性肝癌类型。HCC细胞消耗大量谷氨酰胺来生存，但在外源天冬酰胺存在的情况下可以适应谷氨酰胺的消耗。l -天冬酰胺酶（ASNase）分别将谷氨酰胺和天冬酰胺转化为谷氨酸和天冬氨酸，并已被用于治疗白血病。在这里，我们研究了ASNase对HCC细胞的治疗作用，并探讨了ASNase与酪氨酸激酶抑制剂lenvatinib （Len）联合治疗HCC的潜在影响。观察Len或ASNase单独或Len和ASNase联合作用肝癌细胞株的细胞活力和死亡情况。采用实时定量PCR和免疫印迹法检测谷氨酰胺合成酶（GS）和天冬酰胺合成酶（ASNS） mRNA和蛋白表达水平。在异种移植肿瘤小鼠模型中，还评估了联合治疗相对于Len或ASNase单药治疗的抗肿瘤效果。ASNase处理对GS低表达的SNU387和高表达的SNU398肝癌细胞的生长有抑制作用，而对其他细胞系的生长无明显抑制作用。Len + ASNase联合治疗可协同抑制肝癌细胞系的增殖并诱导氧化应激导致细胞死亡。然而，表达ASCT2（癌细胞重要的谷氨酰胺转运体）的Huh7细胞的细胞死亡不受联合治疗的影响。在异种移植模型中，相对于单独使用Len或ASNase治疗的小鼠，Len联合ASNase显著减轻了肿瘤的发展。asnase介导的两种氨基酸，谷氨酰胺和天冬酰胺，是HCC生存所必需的，可诱导氧化应激，与Len联合使用可产生协同效应，是一种新的癌症治疗选择。
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.
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影响因子：
8.8
作者：
Chiu, M.;Tardito, S.;Pillozzi, S.;Arcangeli, A.;Armento, A.;Uggeri, J.;Missale, G.;Bianchi, M. G.;Barilli, A.;Dall'Asta, V.;Campanini, N.;Silini, E. M.;Fuchs, J.;Armeanu-Ebinger, S.;Bussolati, O.
通讯作者：
Bussolati, O.
影响因子：
29
作者：
Michael, Adeola O. Adebayo;Ko, Sungjin;Monga, Satdarshan P.
通讯作者：
Monga, Satdarshan P.
影响因子：
5.2
作者：
Chuma, Makoto;Uojima, Haruki;Maeda, Shin
通讯作者：
Maeda, Shin
影响因子：
29
作者：
Pavlova NN;Hui S;Ghergurovich JM;Fan J;Intlekofer AM;White RM;Rabinowitz JD;Thompson CB;Zhang J
通讯作者：
Zhang J
影响因子：
7.3
作者：
Menon S;Yecies JL;Zhang HH;Howell JJ;Nicholatos J;Harputlugil E;Bronson RT;Kwiatkowski DJ;Manning BD
通讯作者：
Manning BD