Abstract
Metastasis is the leading cause of breast cancer fatalities. To develop new therapeutic strategies, the mechanisms underlying breast cancer invasion and metastasis need to be further investigated. Peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) is a U-box-type E3 ubiquitin ligase belonging to the cyclophilin family. Proteins within this family are the major cytosolic binding proteins of the immunosuppressant drug cyclosporine A (CsA). Although PPIL2 has been reported to potentially be involved in cell migration, its role in breast cancer is still unclear. Herein, we demonstrate that PPIL2 suppressed metastasis in a breast cancer model by altering cell morphology and suppressing the epithelial–mesenchymal transition (EMT) process. Moreover, elevated PPIL2 inhibited EMT and breast cancer invasion by interacting with the classical EMT transcription factor, SNAI1, to enhance its ubiquitin-dependent degradation. Furthermore, PPIL2 protein level and stability was upregulated after CsA treatment, indicating that PPIL2 might be involved in CsA-mediated repression of EMT in breast cancer. Analysis of tissue samples taken from breast cancer patients showed a significant correlation between the expression of PPIL2 and the degree of cancer invasion and metastasis. In summary, these results would shed light on a potential clinical use of CsA in breast cancer patients.
Highlights
Breast cancer is the most frequently diagnosed cancer in females worldwide, with a high mortality rate[1,2,3]
PPIL2 alters cell morphology and suppresses metastasis in breast cancer cells To investigate the function of PPIL2 in breast cancer, the expression of PPIL2 was first measured in MCF10A, MCF-7, T47D, and ZR-75-30
When transfected with FlagPPIL2, which could be taken as siRNA-resistant PPIL2 isoform, the effect of siPPIL2 on cell morphology was restored (Fig. 1c, j)
Summary
Breast cancer is the most frequently diagnosed cancer in females worldwide, with a high mortality rate[1,2,3]. Metastasis is the final stage of cancer progression where the carcinoma has progressed to a higher pathological grade of malignancy, and is generally the leading cause of breast cancer-related death[4]. It is clear that the epithelial–mesenchymal transition (EMT), where cancer cells typically alter their shape and migrate through the extracellular matrix, is common in cancer invasion and metastasis. CsA inhibits breast cancer cell growth[8,9,10], Official journal of the Cell Death Differentiation Association
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