Manipulating RKIP reverses the metastatic potential of breast cancer cells
Trang Huyen Lai1, Mahmoud Ahmed1, Jin Seok Hwang1
1Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.
Abstract:
Breast cancer is a common tumor type among women, with a high fatality due to metastasis. Metastasis suppressors encode proteins that inhibit the metastatic cascade independent of the primary tumor growth. Raf kinase inhibitory protein (RKIP) is one of the promising metastasis suppressor candidates. RKIP is reduced or lost in aggressive variants of different types of cancer. A few pre-clinical or clinical studies have capitalized on this protein as a possible therapeutic target. In this article, we employed two breast cancer cells to highlight the role of RKIP as an antimetastatic gene. One is the low metastatic MCF-7 with high RKIP expression, and the other is MDA-MB-231 highly metastatic cell with low RKIP expression. We used high-throughput data to explore how RKIP is lost in human tissues and its effect on cell mobility. Based on our previous work recapitulating the links between RKIP and SNAI, we experimentally manipulated RKIP in the cell models through its novel upstream NME1 and investigated the subsequent genotypic and phenotypic changes. We also demonstrated that RKIP explained the uneven migration abilities of the two cell types. Furthermore, we identified the regulatory circuit that might carry the effect of an existing drug, Epirubicin, on activating gene transcription. In conclusion, we propose and test a potential strategy to reverse the metastatic capability of breast cancer cells by chemically manipulating RKIP expression.
Insights
This study highlights Raf kinase inhibitory protein (RKIP) as a metastasis suppressor in breast cancer. Manipulating RKIP expression offers a potential strategy to reverse cancer cell metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis Research
Background:
- Breast cancer metastasis is a significant cause of mortality.
- Metastasis suppressors, like Raf kinase inhibitory protein (RKIP), inhibit cancer spread.
- RKIP expression is often reduced in aggressive cancers, indicating its suppressive role.
Purpose of the Study:
- To elucidate the antimetastatic role of RKIP in breast cancer models.
- To investigate the mechanisms underlying RKIP loss and its impact on cell mobility.
- To explore therapeutic strategies targeting RKIP for reversing breast cancer metastasis.
Main Methods:
- Utilized two breast cancer cell lines: MCF-7 (low metastatic, high RKIP) and MDA-MB-231 (high metastatic, low RKIP).
- Employed high-throughput data analysis to examine RKIP loss in human tissues.
- Experimentally manipulated RKIP expression via its upstream regulator NME1 to assess genotypic and phenotypic changes.
- Investigated the regulatory circuit involving RKIP and potential drug interactions (Epirubicin).
Main Results:
- RKIP expression levels correlated inversely with breast cancer cell metastatic potential.
- RKIP manipulation altered cell mobility and genotypic/phenotypic characteristics.
- Identified a regulatory circuit potentially influenced by Epirubicin, affecting gene transcription.
Conclusions:
- RKIP functions as a critical antimetastatic gene in breast cancer.
- Experimental manipulation of RKIP can reverse metastatic capabilities.
- Targeting RKIP presents a promising therapeutic strategy for combating breast cancer metastasis.
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