Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response.
Hypoxia stimulates migration of breast cancer cells via the PERK/ATF4/LAMP3-arm of the unfolded protein response.
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DOI：
10.1186/bcr3373
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发表时间：
2013-01-07
期刊：
影响因子：
--
通讯作者：
Span PN
中科院分区：
文献类型：
--
作者：
Nagelkerke A;Bussink J;Mujcic H;Wouters BG;Lehmann S;Sweep FC;Span PN
缺氧诱导因子（HIF）-1通路可刺激肿瘤细胞的迁移和转移。此外，缺氧肿瘤与不良预后相关。除了HIF-1通路，未折叠蛋白反应（UPR）也由缺氧条件诱导。UPR的PKR样ER激酶（PERK）/活化转录因子4（ATF 4）臂诱导溶酶体相关膜蛋白3（LAMP 3）的表达，该因子与实体瘤中的转移和不良预后有关。在这项研究中，检查了UPR诱导的LAMP3在缺氧介导的乳腺癌细胞迁移中的作用。采用多种体外转移模型研究MDA-MB-231乳腺癌细胞在低氧条件下的迁移和侵袭。PERK、ATF 4及其下游因子LAMP 3被敲低以检查它们在细胞迁移中的作用。此外，多细胞肿瘤球体被用于研究肿瘤微环境在侵袭中的参与。使用transwell分析，评估不同乳腺癌细胞系的迁移。发现细胞迁移和基线LAMP3表达之间存在直接相关性。此外，中度缺氧（1%O2）被认为是最佳的刺激MDA-MB-231细胞的迁移。siRNA介导的PERK、ATF 4和LAMP 3的敲低减少了这些条件下的细胞迁移。在胶原蛋白的三维侵入试验中，当在多细胞球体中共同生长时，与对照细胞相比，LAMP3敲低细胞显示出侵入能力减弱。因此，UPR的PERK/ATF4/LAMP3臂是介导缺氧诱导的乳腺癌细胞迁移的额外途径。
The hypoxia-inducible factor (HIF)-1 pathway can stimulate tumor cell migration and metastasis. Furthermore, hypoxic tumors are associated with a poor prognosis. Besides the HIF-1 pathway, the unfolded protein response (UPR) is also induced by hypoxic conditions. The PKR-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-arm of the UPR induces expression of lysosomal-associated membrane protein 3 (LAMP3), a factor that has been linked to metastasis and poor prognosis in solid tumors. In this study the role of UPR-induced LAMP3 in hypoxia-mediated migration of breast cancer cells was examined. A number of in vitro metastasis models were used to study the migration and invasion of MDA-MB-231 breast cancer cells under hypoxic conditions. PERK, ATF4 and their downstream factor LAMP3 were knocked down to examine their role in cell migration. In addition, multicellular tumor spheroids were used to study the involvement of the tumor microenvironment in invasion. Using transwell assays, migration of different breast cancer cell lines was assessed. A direct correlation was found between cell migration and baseline LAMP3 expression. Furthermore, moderate hypoxia (1% O2) was found to be optimal in stimulating migration of MDA-MB-231 cells. siRNA mediated knockdown of PERK, ATF4 and LAMP3 reduced migration of cells under these conditions. Using gap closure assays, similar results were found. In a three-dimensional invasion assay into collagen, LAMP3 knockdown cells showed a diminished capacity to invade compared to control cells when collectively grown in multicellular spheroids. Thus, the PERK/ATF4/LAMP3-arm of the UPR is an additional pathway mediating hypoxia-induced breast cancer cell migration.
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