Abstract

Effects of amyloid beta (Aβ) oligomers on viability and function of cell lines such as NB4 (human acute promyelocytic leukemia), A549 (human lung cancer (adenocarcinomic alveolar basal epithelial tumor)) and MCF-7 (human breast cancer (invasive breast ductal carcinoma)) were investigated. Two types of Aβ oligomers were used in the study. The first type was produced in the presence of oligomerization inhibitor, hexafluoroisopropanol (HFIP). The second type of amyloids was assembled in the absence of the inhibitor. The first type preparation was predominantly populated with dimers and trimers, while the second type contained mostly pentadecamers. These amyloid species exhibited different secondary protein structure with considerable amount of antiparallel β sheet structural elements in HFIP oligomerized Aβ mixtures. The effect of the cell growth inhibition, which was stronger in the case of HFIP Aβ oligomers, was observed for all cell lines. Tests aiming at elucidating the effects of the amyloid species on cell cycles showed little differences between amyloid preparations. This prompts us to conclude that the effect on the cancer cell proliferation rate is less specific to the biological processes developing inside the cells during the proliferation. Therefore, cell growth inhibition may involve interactions with the peripheral parts of the cancer cells, such as a phospholipid membrane, and only in case of the NB4 cells, where accumulation of amyloid species inside the cells was detected, one may imply the opposite. In general, cancer cells were much less susceptible to the damaging effects of amyloid oligomers compared to earlier observations in mixed neuronal cell cultures.

Highlights

  • Short, 4.5 kDa amyloid-β (Aβ) peptide is produced in the brain

  • We demonstrated that in human lung cancer cell line A549 after 24 hour treatment with amyloids prepared by HFIP protocol the cell accumulation in S phase was increased app. by 4% and after 48-hours of treatment cell arrest in G2/M cell cycle phase was observed

  • The molecular weight estimate performed via calibration of the chromatographic column as described in the supporting material S1 Appendix suggests pentadecamers are the main component of the HFIP-free amyloid preparation

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Summary

Introduction

4.5 kDa amyloid-β (Aβ) peptide is produced in the brain. It is a by-product of the biochemical processing of the abundant amyloid precursor protein (APP), which functions in the brain. Despite its involvement in numerous biological processes, its function and biochemical processing are not fully understood [1, 2]. The normal processing of APP is carried out by the α-secretase which releases a large soluble extracellular domain sAPP-α which possibly undergoes further degradation by extracellular proteases [3].

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