Integrin-independent support of cancer drug resistance by tetraspanin CD151
Integrin-independent support of cancer drug resistance by tetraspanin CD151
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DOI：
10.1007/s00018-019-03014-7
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发表时间：
2019-04-01
影响因子：
8
通讯作者：
Hemler, Martin E.
中科院分区：
文献类型：
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作者：
Hwang, Soonyean;Takimoto, Takayuki;Hemler, Martin E.
Tetraspanin蛋白CD151通常被研究为层粘连蛋白结合整合素的结合伙伴和功能调节因子。然而，我们在这里表明，CD151支持独立于整合素的抗癌药物耐药性。CD151消融使多种类型的肿瘤细胞对几种抗癌药物(如吉非替尼和喜树碱)增敏，从而增加细胞凋亡，通过裂解caspase-3、裂解PARP(聚(ADP-核糖)聚合酶)、膜联蛋白V和碘化丙啶染色分析发现。CD151消融引起的药物增敏是非整合素依赖的，因为：(1)当整合素与配体脱节时，在细胞中发生作用，(2)整合素消融(3和6亚基)不能模仿CD151消融的效果，(3)CD151(QRD)突变体，整合素结合减弱，CD151(WT)(未突变的CD151)类似的重组药物保护，以及(4)抗癌药物治疗选择性上调细胞内非整合素相关CD151(NIA-CD151)，与其在耐药中的作用一致。综上所述，这些结果表明，在抗癌药物治疗期间，上调的CD151表达不仅可能支持典型的整合素依赖功能，而且可能支持循环(以及可能转移)癌细胞的整合素非依赖性生存。
Tetraspanin protein CD151 has typically been studied as binding partner and functional regulator of laminin-binding integrins. However, we show here that CD151 supports anti-cancer drug resistance independent of integrins. CD151 ablation sensitized multiple tumor cell types to several anti-cancer drugs (e.g., gefitinib and camptothecin), thus increasing apoptosis, as seen using cleaved caspase-3, cleaved PARP (poly (ADP-ribose) polymerase), annexin V, and propidium iodide staining assays. Drug sensitization due to CD151 ablation is integrin-independent, because, (1) effects occurred in cells when integrins were unengaged with ligand, (2) integrin ablation (3 and 6 subunits) did not mimic effects of CD151 ablation, (3) the CD151(QRD) mutant, with diminished integrin association, and CD151(WT) (unmutated CD151) similarly reconstituted drug protection, and (4) treatment with anti-cancer drugs selectively upregulated intracellular nonintegrin-associated CD151 (NIA-CD151), consistent with its role in drug resistance. Together, these results suggest that upregulated CD151 expression may support not only typical integrin-dependent functions, but also integrin-independent survival of circulating (and possibly metastatic) cancer cells during anti-cancer drug therapy.