Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA.
University of Southern California Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
Life Sci Alliance. 2019 Aug 15;2(4). doi: 10.26508/lsa.201900377. Print 2019 Aug.
GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.
GRP78 在 ER 中进行蛋白质折叠和质量控制，并在晚期肿瘤中表现出高表达和细胞表面易位。然而，使 GRP78 能够在细胞表面发挥新的信号转导功能的潜在机制才刚刚出现。CD44 是一种跨膜蛋白，是癌症转移的重要调节剂，在癌症进展过程中，CD44 通过将额外的可变外显子掺入细胞外近膜区，经常发生异构体转换。使用超分辨率双色单颗粒跟踪技术，我们报告 GRP78 在乳腺癌细胞膜纳米域与 CD44v 相互作用。我们进一步表明，通过抗体靶向细胞表面 GRP78 可以有效降低 tamoxifen 耐药乳腺癌细胞表面 CD44v 的表达和细胞铺展。我们的结果揭示了 GRP78 作为 CD44v 的相互作用伙伴以及作为 CD44v 膜动态平衡和细胞铺展的调节剂的新功能。这项研究还为 tamoxifen 耐药乳腺癌的抗 CD44 治疗提供了新的见解。
