ICAM-3 endows anticancer drug resistance against microtubule-damaging agents via activation of the ICAM-3-AKT/ERK-CREB-2 pathway and blockage of apoptosis
ICAM-3 endows anticancer drug resistance against microtubule-damaging agents via activation of the ICAM-3-AKT/ERK-CREB-2 pathway and blockage of apoptosis
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DOI：
10.1016/j.bbrc.2013.10.096
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发表时间：
2013-11-15
影响因子：
3.1
通讯作者：
Um, Hong-Duck
中科院分区：
文献类型：
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作者：
Ahn, Kwang-Chul;Choi, Jae Yeon;Um, Hong-Duck
在先前的研究中，我们发现ICAM-3的诱导赋予宫颈癌放射抗性[1]。为了确定ICAM-3是否也促进抗癌药物耐药性，产生了非小细胞肺癌（NSCLC）细胞系NCI-H1299的模拟对照（H1299/pcDNA 3）或表达ICAM-3的稳定转染子（H1299/ICAM-3），并用微管损伤剂紫杉醇（TXL）和长春新碱（VCS）处理。与H1299/pcDNA 3细胞相比，TXL-/VCS处理的H1299/ICAM-3细胞显示出显著较低的凋亡水平，半胱氨酸蛋白酶-3，8或9的活化，以及抗凋亡蛋白水平的降低。我们的数据清楚地表明，ICAM-3通过抑制细胞凋亡促进耐药性。我们还发现，Akt、ERK和CREB-2位于ICAM-3的下游，ICAM-3-Akt/ERK-CREB-2通路的激活诱导了对TXL和THP的抗性。ICAM-3表达稳定的NCI-H460/ICAM-3转染细胞和内源性过表达ICAM-3的放射抗性SiHa细胞还通过激活ICAM-3-Akt/ERK-CREB-2途径显示出对TXL和TXL的耐药性。ICAM-3具有耐药性和耐辐射性，这一发现支持其作为癌症主要治疗靶点的潜在用途。(C)2013 Elsevier Inc. All rights reserved.
In a previous study, we showed that induction of ICAM-3 endows radioresistance in cervical cancer [1]. To ascertain whether ICAM-3 also promotes anticancer drug resistance, mock control (H1299/pcDNA3) or ICAM-3-expressing stable transfectants (H1299/ICAM-3) of the non-small cell lung cancer (NSCLC) cell line, NCI-H1299, were generated and treated with the microtubule-damaging agents, paclitaxel (TXL) and vincristine (VCS). TXL-/VCS-treated H1299/ICAM-3 cells showed significantly lower levels of apoptosis, activation of caspases-3, 8 or 9, and decrease in anti-apoptotic protein levels, compared to H1299/pcDNA3 cells. Our data clearly indicate that ICAM-3 promotes drug resistance via inhibition of apoptosis. We additionally showed that Akt, ERK, and CREB-2 are located downstream of ICAM-3, and activation of the ICAM-3-Akt/ERK-CREB-2 pathway induces resistance against TXL and VCS. ICAM-3-expressing stable NCI-H460/ICAM-3 transfectant cells and radioresistant SiHa cells endogenously overexpressing ICAM-3 additionally showed drug resistance against TXL and VCS via activation of the ICAM-3-Akt/ERK-CREB-2 pathway. The finding that ICAM-3 endows drug resistance as well as radioresistance supports its potential utility as a major therapeutic target against cancer. (C) 2013 Elsevier Inc. All rights reserved.