Role of HtrA1 in cell migration and metastasis Free

LB-274

Metastasis, one of the most significant steps in the progression of cancer, is also the most lethal aspects of cancer. Metastasis and the failure of chemotherapy to treat metastatic disease are the primary causes of cancer-related mortality. One of the critical components in metastasis is the ability of cancer cells to migrate into surrounding tissues and tumor vasculatures. Here we reports that HtrA1, a serine protease previously identified as down-regulated in ovarian cancer and metastatic melanoma, associates with cytoskeletal microtubules, inhibits microtubules assembly, and affects cancer cell motility. HtrA1 localizes to microtubules, and co-precipitates and co-purifies with tubulins. Immunoprecipitation of HtrA1 resulted in co-immunoprecipitation of alpha-, beta-, and gamma-tubulins. Furthermore, purified HtrA1 inhibits in vitro tubulin polymerization. Forced expression of HtrA1 attenuates cancer cell migration, whereas down-regulation of endogenous HtrA1 by RNAi promotes cell motility. Moreover, endogenous HtrA1 inhibits fibronectin-mediated cell spreading without affecting collagen-mediated cell spreading. Finally, immunohistochemical analysis of HtrA1 expression in 67 primary ovarian tumors, 100 primary breast tumors and corresponding 58 nodal metastases, and 100 primary colorectal cancers and corresponding 70 nodal metastases indicates that down-regulation of HtrA1 is associated with metastatic phenotypes of ovarian, breast and colorectal cancers. These results uncover a novel and specific role of HtrA1 in cancer cell migration through its association with cytoskeletal microtubules, and offer initial mechanistic insights into how this protein may modulate cell migration and metastasis.