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Albumin fusion with human lactoferrin shows enhanced inhibition of cancer cell migration

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Abstract

The fusion of human serum albumin (HSA) with human lactoferrin (hLF) (designated as hLF-HSA) has improved the pharmacokinetic properties and anti-proliferative activities of hLF against cancer cells. In this study, we evaluated the anti-migratory activities of hLF and hLF-HSA against the human lung adenocarcinoma PC-14 cell line using wound healing and Boyden chamber assays. Despite the unexpected hLF-induced migration, hLF-HSA clearly demonstrated the complete inhibition of PC-14 cell migration. To examine the mechanism underlying the enhanced PC-14 cell migration by hLF alone but suppressed migration by hLF-HSA, we focused on the matrix metalloproteinase (MMP) family of endopeptidases because MMPs are often reported to play important roles in facilitating the migration and metastasis of cancer cells. Furthermore, hLF is a transactivator of MMP1 transcription. As expected, treatment of cells with hLF and hLF-HSA led to the upregulation and downregulation of MMP1, respectively. In contrast, MMP9 expression levels, which are often associated with cancer migration, were unchanged in the presence of either protein. An MMP inhibitor attenuated hLF-induced migration of PC-14 cells. Therefore, specific enhancement and suppression of MMP1 expression by hLF and hLF-HSA have been implicated as causes of a marked increase and decrease in PC-14 cell migration, respectively. In conclusion, the fusion of HSA with hLF (hLF-HSA) promoted its anti-migratory effects against cancer cells. Therefore, hLF-HSA is a promising anti-cancer drug candidate based on its improved anti-migratory activity towards cancer cells.

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Acknowledgements

The authors thank Hiroto Ishida (School of Bioscience and Biotechnology, Tokyo University of Technology) for providing technical assistance. We are grateful to Prof. Yuko Murakami (School of Bioscience and Biotechnology, Tokyo University of Technology), Dr. Misa Imai (Graduate School of Medicine, Juntendo University, Tokyo, Japan), and Dr. Masao Nakamura (Sasaki Institute, Sasaki Foundation, Tokyo, Japan) for their useful discussions.

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This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

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HN: investigation, writing, review, and editing. DK: investigation and review. AS: conceptualization, writing, reviewing, editing, and supervision. All authors reviewed the manuscript.

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Correspondence to Atsushi Sato.

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A. Sato was the founder of S&K Biopharma Inc. (Kawasaki, Kanagawa, Japan).

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Nopia, H., Kurimoto, D. & Sato, A. Albumin fusion with human lactoferrin shows enhanced inhibition of cancer cell migration. Biometals 36, 629–638 (2023). https://doi.org/10.1007/s10534-022-00447-9

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  • DOI: https://doi.org/10.1007/s10534-022-00447-9

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