Intrinsic and chemically-induced daughter number variations in cancer cell lines

ABSTRACT

Multipolar mitosis was observed in cancer cells under mechanical stress or drug treatment. However, a comprehensive understanding of its basic properties and significance to cancer cell biology is lacking. In the present study, live-cell imaging was employed to investigate the division and nucleation patterns in four different cell lines. Multi-daughter divisions were observed in the three cancer cell lines HepG2, HeLa and A549, but not in the transformed non-cancer cell line RPE1. Multi-daughter mother cells displayed multi-nucleation, enlarged cell area, and prolonged division time. Under acidic pH or treatment with the anti-cancer drug 5-fluorouracil (5-FU) or the phytochemical compound wogonin, multi-daughter mitoses were increased to different extents in all three cancer cell lines, reaching as high as 16% of all mitoses. While less than 0.4% of the bi-daughter mitosis were followed by cell fusion events under the various treatment conditions, 50% or more of the multi-daughter mitoses were followed by fusion events at neutral, acidic or alkaline pH. These findings revealed a “Daughter Number Variation” (DNV) process in the cancer cells, with multi-daughter divisions in Stage 1 and cell fusions leading to the formation of cells containing up to five nuclei in Stage 2. The Stage 2-fusions were inhibited by 5-FU in A549 and HeLa, and by wogonin in A549, HeLa and HepG2. The parallel relationship between DNV frequency and malignancy among the different cell lines suggests that the inclusion of anti-fusion agents exemplified by wogonin and 5-FU could be beneficial in combinatory cancer chemotherapies.

KEYWORDS:

• Cancer
• cell fusion
• multi-daughter division
• wogonin
• 5-fluorouracil

Authors’ contributions

Conception and design: H. Xue, I.S. Tyagi,

Development of methodology: I.S. Tyagi, H. Xue

Acquisition of the data: I.S. Tyagi, M.A. Khan, J. Xie, P.Y. Li, S. Chen

Analysis and interpretation of data: I.S. Tyagi, S. Chen, X. Long, H. Xue

Writing, review, and/or revision of the manuscript: I.S. Tyagi, H. Xue

Study supervision: H. Xue

Disclosure statement

The authors declare that they have no competing interests.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This work was supported by the Innovation and Technology Commission under Grant (ITS/113/15FP; ITT/023/17GP; ITT/026/18GP) and the University Grants Committee (VPRDO09/10.SC08; DG17SC01; SRF111EG01; SRF111EG04PG) of Hong Kong Special Administrative Region, and Science, Technology and Innovation Commission of Shenzhen Municipality, China (SZ-SZST11808), and Department of Science and Technology of Guangdong Province, People’s Republic of China”. I. Shazia was the recipient of a Postgraduate Studentship from Hong Kong University of Science and Technology.