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eHsp90alpha and clusterin synergistically promote breast cancer epithelial-to-mesenchymal transition and metastasis via LRP1.
Tian, Y.; Wang, C.; Chen, S. (...)
【来源】:Journal of cell science, 2019,
【摘要】:Extracellular heat shock protein 90 alpha (eHsp90alpha) has been widely reported to promote tumor cell motility and tumor metastasis in various types of cancer. Several extracellular proteins and membrane receptors have been identified as interacting proteins of eHsp90alpha and mediate its pro-metastasis function. However, the regulatory mechanism of eHsp90alpha activity remains largely unknown. Here, we reported that clusterin, a novel interacting protein of eHsp90alpha, modulated eHsp90alpha signaling. We found that clusterin potentiated the effects of eHsp90alpha on the activation of AKT, ERK, NF-kappaB, epithelial-to-mesenchymal transition (EMT) and migration in breast cancer cells. Furthermore, in vivo investigations demonstrated similar synergistic effects of eHsp90alpha and clusterin on tumor metastasis. Notably, the effects of eHsp90alpha and clusterin were mediated by low-density lipoprotein receptor-related protein 1 (LRP1). Proximity ligation assay and co-immunoprecipitation experiments demonstrated that clusterin participated in the complex formation of eHsp90alpha and LRP1, which enhanced the binding affinity of eHsp90alpha to LRP1. Collectively, our data establish a role of clusterin as a novel modulator of eHsp90alpha, and unravel detailed molecular mechanisms underlying the synergistic metastasis-promoting effects of clusterin and eHsp90alpha.