☆ 4.6 Article

The subcellular location of cyclin B1 and CDC25 associated with the formation of polyploid giant cancer cells and their clinicopathological significance

LABORATORY INVESTIGATION (2019)

Journal

LABORATORY INVESTIGATION

Volume 99, Issue 4, Pages 483-498

Publisher

NATURE PUBLISHING GROUP

DOI: 10.1038/s41374-018-0157-x

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Funding

National Science Foundation of China [81472729, 81672426]
foundation of committee on science and technology of Tianjin [17YFZCSY00700, 17ZXMFSY00120]

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Abstract

Polyploid giant cancer cells (PGCCs) are key contributors to cancer heterogeneity, and the formation of PGCCs is associated with changes in the expression of cell-cycle-related proteins. This study investigated the intracellular localization and expression level of multiple cell-cycle-related proteins in PGCCs derived from BT-549 and HEY cells. In addition, the formation of PGCCs and the clinicopathological significance of cell-cycle-related proteins in human breast and ovarian cancer were examined. The expression levels of cell-cycle-related proteins, including cyclin B1, CDC25B, CDC25C, and other cell cycle phosphoproteins, including Chk2, and Aurora-A kinase, were determined using immunostaining and western blotting both in vitro and in vivo. Migration, invasion, and proliferation in control cells, cyclin B1 knockdown cells and their PGCCs following CoCl2 treatment were compared. In addition, human breast and ovarian cancer samples were collected to determine the correlation of number of PGCCs, expression of cell-cycle-related proteins, and tumor pathologic grade and metastasis. Our results confirm that cyclin B1 was localized in the cytoplasm of PGCCs and in the nuclei of their budding daughter cells. The phosphorylated proteins Chk2 and Aurora-A kinase regulated the expression and subcellular localization of cyclin B1, CDC25B, and CDC25C. The rate of positive cytoplasmic staining of cyclin B1 and positive nuclear staining of both CDC25B and CDC25C increased with increase in tumor grade and lymph node metastasis. Cell-cycle-related proteins, including cyclin B1, CDC25B, and CDC25C play an important role in regulating the formation of PGCCs. The inhibition of cyclinB1 and CoCl(2 )treatment significantly promoted cell proliferation, invasion, and migration abilities. The subcellular localization of these cell-cycle-related proteins was regulated by other cell cycle phosphoproteins, and was associated with pathologic grade and metastasis of tumors in cases of human breast and ovarian cancer.

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Cytoplasmic SIRT1 promotes paclitaxel resistance in ovarian carcinoma through increased formation and survival of polyploid giant cancer cells

Hong Xu, Shujun Zeng, Yingmei Wang, Tong Yang, Minmin Wang, Xuan Li, Yejun He, Xin Peng, Xia Li, Qing Qiao, Jing Zhang

Summary: Therapeutic resistance is a common cause of death in ovarian carcinoma patients. Polyploid giant cancer cells (PGCCs) are believed to play a role in drug resistance following chemotherapy. Sirtuin1 (SIRT1), a type III deacetylase, is involved in cell cycle, cellular senescence, and drug resistance. This study investigated the impact of SIRT1 subcellular localization on PGCC formation, senescence escape, and response to paclitaxel treatment in ovarian carcinoma cells. The results indicated that cytoplasmic SIRT1 affects PGCC formation and survival, contributing to paclitaxel resistance.

JOURNAL OF PATHOLOGY (2023)