Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression.
Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression.
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DOI：
10.1038/s41419-022-04520-6
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发表时间：
2022-01-24
影响因子：
9
通讯作者：
Troncoso MF
中科院分区：
文献类型：
--
作者：
Carabias P;Espelt MV;Bacigalupo ML;Rojas P;Sarrias L;Rubin A;Saffioti NA;Elola MT;Rossi JP;Wolfenstein-Todel C;Rabinovich GA;Troncoso MF
半乳糖凝集素-1（Galectin-1，GAL 1）是一种在肿瘤微环境中大量表达的β-半乳糖苷结合蛋白，是肿瘤耐药的重要机制。虽然GAL 1表达增加是肝细胞癌（HCC）进展、侵袭性和转移的标志，但关于这种内源性凝集素在HCC对化疗耐药中的作用的信息有限。此外，这种效应背后的确切机制尚不确定。HCC已经进化出不同的化疗耐药机制，包括涉及P-糖蛋白（P-gp）的机制，P-糖蛋白是一种ATP依赖性药物外排泵，控制细胞内药物浓度。在这里，我们研究了肝细胞癌细胞中GAL 1介导的化疗耐药的分子机制，特别是P-gp在这种作用中的参与。我们的研究结果表明，GAL 1保护HepG 2细胞从阿霉素（DOX）和索拉非尼诱导的细胞死亡在体外。因此，GAL 1过表达的HepG 2细胞在体内产生了DOX抗性肿瘤。GAL 1在HepG 2细胞中的高表达可能通过增加P-gp蛋白表达而不是改变其膜定位来减少DOX的细胞内积聚。GAL 1介导的P-gp表达增加涉及磷脂酰肌醇-3激酶（PI 3 K）信号通路的激活。此外，“功能丧失”实验表明，在HepG 2细胞中，P-gp介导GAL 1驱动的对DOX的抗性，但不介导对索拉非尼的抗性。相反，在PLC/PRF/5细胞中，P-gp蛋白表达检测不到，GAL 1不控制对DOX或索拉非尼的耐药性，支持P-gp在介导GAL 1效应中的关键作用。总的来说，我们的研究结果表明，GAL 1赋予肝癌化疗耐药的机制，涉及P-gp的调制，从而强调了这种凝集素作为一个潜在的治疗靶点在肝癌的作用。
Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, ‘loss-of-function’ experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.
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影响因子：
4.6
作者：
Blaževitš O;Mideksa YG;Šolman M;Ligabue A;Ariotti N;Nakhaeizadeh H;Fansa EK;Papageorgiou AC;Wittinghofer A;Ahmadian MR;Abankwa D
通讯作者：
Abankwa D
影响因子：
9
作者：
Clemente, Tiago;Vieira, Narcisio J.;Amarante-Mendes, Gustavo P.
通讯作者：
Amarante-Mendes, Gustavo P.
DOI：
10.1016/j.bbamcr.2019.03.010
发表时间：
2019-08-01
影响因子：
5.1
作者：
Ferragut, Fatima;Cagnoni, Alejandro J.;Elola, Maria T.
通讯作者：
Elola, Maria T.
影响因子：
5.1
作者：
Gao, Jie;Wang, Wenying
通讯作者：
Wang, Wenying
影响因子：
4.2
作者：
Korita, Pavel V.;Wakai, Toshifumi;Ajioka, Yoichi
通讯作者：
Ajioka, Yoichi