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Inhibition of filamin-A reduces cancer metastatic potential.

ABSTRACT: Filamin-A cross-links actin filaments into dynamic orthogonal networks, and interacts with an array of proteins of diverse cellular functions. Because several filamin-A interaction partners are implicated in signaling of cell mobility regulation, we tested the hypothesis that filamin-A plays a role in cancer metastasis. Using four pairs of filamin-A proficient and deficient isogenic cell lines, we found that filamin-A deficiency in cancer cells significantly reduces their migration and invasion. Using a xenograft tumor model with subcutaneous and intracardiac injections of tumor cells, we found that the filamin-A deficiency causes significant reduction of lung, splenic and systemic metastasis in nude mice. We evaluated the expression of filamin-A in breast cancer tissues by immunohistochemical staining, and found that low levels of filamin-A expression in cancer cells of the tumor tissues are associated with a better distant metastasis-free survival than those with normal levels of filamin-A. These data not only validate filamin-A as a prognostic marker for cancer metastasis, but also suggest that inhibition of filamin-A in cancer cells may reduce metastasis and that filamin-A can be used as a therapeutic target for filamin-A positive cancer.

SUBMITTER: Jiang X

PROVIDER: S-EPMC3535535 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Non-Small Cell Lung Cancer (NSCLC) presents as a highly metastatic disease with Kras and P53 as prevalent oncogenic driver mutations. Endocytosis, through its role in receptor recycling and enrichment, is important for cancer cell proliferation and metastasis. Huntingtin Interacting Protein 1 (HIP1) is a clathrin mediated endocytic adapter protein found overexpressed in different cancers. However, conflicting roles both as a tumour promoter and suppressor are reported. HIP1 expression is found repressed at advanced stages and some HIP1-ALK fusions are reported in NSCLC patients. However, the molecular mechanisms and implications of HIP1 depletion are not completely understood. Methods: HIP1 depletion was performed using siRNA transient transfection and validated using immunoblotting for each experiment. HIP1 depleted A549 cells were analysed for deregulated global proteome using label-free LC-MS. Gene expression dataset was analysed using TCGA, GTeX and GEO to explore HIP1 expression in Lung cancer patients. Kaplan–Meier Plotter database was used to analyse the survival correlation between HIP1 mRNA expression in lung cancer patients. Various functional assays such as matrigel based invasion, trans-well migration, soft agar colony, tube formation are performed after HIP1 depletion. NRF2 inhibitor was used after HIP1 knockdown to assess its effect on invasion and soft agar colony formation. Results: In silico analysis of HIP1 transcript expression reveals that it is reduced in high-grade and metastatic lung cancer patients correlating with poor survival. Global proteome profiling reveals that HIP1 depleted A549 cells are enriched in pathways associated with metabolism, proliferation and survival. Molecular and functional analysis indicate higher invasive ability of HIP1 depleted cells. The secretome from HIP1 depleted cells also increases the angiogenic potential of HUVEC cells. NRF2 inhibition in HIP1 depleted cells reduces invasion of NSCLC cells with different driver mutations. Conclusion: Our study shows that HIP1 depletion leads to activation of various molecular pathways responsible for cell proliferation and survival. Additionally, enhancement of invasion in HIP1 depleted subsets of NSCLC cells is via upregulation of NRF2 and can be reversed by its inhibitor.

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Inhibition of filamin-A reduces cancer metastatic potential.

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