Harnessing the chondroitin sulfate-binding characteristics of human lactoferrin to neutralize neurite outgrowth inhibition

Nakamura, Masao; Matsuzaki, Takumi; Iimori, Ami; Sato, Atsushi

doi:10.1016/j.bbrc.2020.10.005

Cited by 5 publications

(2 citation statements)

References 24 publications

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“…17) Therefore, CS-E present on the cancer cell surface may be utilized as a cancer antigen and drug delivery target. Moreover, the N-lobe directly binds to CS-E. 10) However, the role of CS-E in the intracellular uptake of the N-lobe is unknown. Therefore, we verified whether the intracellular uptake of the N-lobe into cancer cells was inhibited by CS-E.…”

Section: Biological and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

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Efficient Endocytosis of the Human Lactoferrin N-Lobe Enhances Its Antiproliferative Activity against Human Cancer Cells

Nakamura

Shiga

Iimori

et al. 2023

Biological & Pharmaceutical Bulletin

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Human lactoferrin (hLF) is a glycosylated globular iron-binding protein with high functional versatility that elicits anticancer, neuroprotective, and anti-inflammatory effects. Some of the diverse functions of hLF are induced after its internalization into various cells via cell surface endocytosis receptors, such as proteoglycans, which contain glycosaminoglycan (GAG) chains.We have previously demonstrated that an hLF derivative comprising the N-terminal half of hLF (referred to as the N-lobe) is internalized by intestinal enterocyte Caco-2 cells. However, the relationship between the intracellular uptake of the N-lobe and its pharmacological activity remains poorly understood. Here, we report that the N-lobe is efficiently internalized by lung cancer cells via endocytic pathways, suppressing their proliferation. Moreover, the N-lobe showed higher intracellular uptake than hLF. We found that the N-lobe was internalized into the human lung cancer cell lines PC-14 and PC-3 via clathrin-and/or caveolae-mediated endocytosis. Intracellular uptake of the N-lobe was inhibited when an equimolar concentration of chondroitin sulfate (CS)-E, a GAG subtype involved in malignant transformation and tumor metastasis, was added. The inhibitory effect of the N-lobe on PC-14 cell proliferation decreased with the addition of CS-E in a dose-dependent manner, suggesting that the CS-recognizing sequence on the N-lobe is necessary for its internalization or that the CS proteoglycan on cancer cells acts as an endocytosis receptor. These results suggest that the efficient endocytic uptake of the N-lobe is important for its antiproliferation effects on lung cancer cell lines. Thus, the N-lobe presents a promising drug candidate for cancer treatment.

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Section: Biological and Pharmaceutical Bulletin Advance Publicationmentioning

confidence: 99%

“…8) We previously demonstrated that the N-lobe is internalized by intestinal enterocyte Caco-2 cells 9) and binds to CS-E, a GAG subtype involved in cancer and neurodegenerative diseases. 10) However, the relationship between the intracellular uptake of the N-lobe and its pharmacological activity remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%