Significance of Altered Golgi Apparatus and Cell Fusion Events in Ovarian Cancer Cells

Ovarian cancer is one of the most lethal gynaecological cancer. Heterogeneity associated with this cancer can be partially attributed to cancer cells being highly multinucleated and polyploid in nature. Stress-induced cytotoxic effects of cisplatin - a chemotherapy drug used to treat ovarian cancer, on subcellular organelles including the ER, mitochondria, nucleus and the cytoskeleton are well known, however, its effect on the structural integrity of the Golgi apparatus and associated alterations in functions are not reported. In this study, the effect of cisplatin on the structure and function of the Golgi apparatus are examined and a novel pathway for cisplatin-induced changes in the Golgi is also reported. Additionally, a mechanism is also proposed for formation of multinucleated ovarian cancer cells and a role for transcription adapter-3 (TADA3)-mediated multinucleation has been suggested. Treatment of ovarian cancer cells with cisplatin resulted in significant fragmentation of the Golgi apparatus with cisplatin-induced Golgi fragmentation detected before cisplatin-induced DNA damage. Inhibition of cisplatin-stress induced activation of c-Jun-N-terminal kinase (JNK) significantly reduced fragmentation of the Golgi in ovarian cancer cells while extracellular signal-regulated kinase (ERK1/2) inhibition significantly increased fragmentation in A2780 cells but had no effect on other cell lines (OVCAR3 and SKOV3) tested. Cells exposed to cisplatin during migration showed significantly depolarised Golgi, reduced cell motility and wound healing capacity. Protein trafficking was also significantly reduced in response to cisplatin. Cell-line specific effect was found on the expression of terminal GalNAc glycans in response to cisplatin. Moreover, ovarian cancer cells were observed to fuse with each other following cell division producing multinucleated cells. Gene expression correlation analysis identified TADA3 as a candidate gene associated with multinuclearity. TADA3 knockdown significantly reduced the number of multinucleated ovarian cancer cells, suggesting a role in cancer cell fusion. In conclusion, this study proposes a novel mode of action for cisplatin-induced cytotoxicity in ovarian cancer cells. Understanding its biology further can open avenues for future treatment options. This study also identifies a novel mechanism for cancer cell fusion. Further investigation in this area can help unravel issues of drug resistance and associated tumour relapse.

Grantor dc:publisher

Oxford Brookes University

Year dc:date

2020

Author dc:creator

• Pradhan, Aditi

Contributors dc:contributor

• Carter, Dave
• Runions, John
• Brooks, Susan

Statement dc:rights

• All rights reserved

Language dc:language

en

DOI dc:identifier

https://doi.org/10.24384/w52q-yj26

OAI identifier oai:identifier

tle:aeeb5842-a18a-468b-9f9f-83db3492aabf:d6bd9758-527a-46cd-bfe2-c433766e8fca:1