FANCD2 expression affects platinum response and further characteristics of high grade serous ovarian cancer in cells with different genetic backgrounds

• Published in: Experimental and molecular pathology 2024-08, Vol.138, p.104916, Article 104916
• Main Authors: Taylor, Sarah J., Hollis, Robert L., Gourley, Charlie, Herrington, C. Simon, Langdon, Simon P., Arends, Mark J.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cancer; Carboplatin - pharmacology; Carboplatin - therapeutic use; Cell Line, Tumor; Cell Movement - genetics; Chemoresistance; Cystadenocarcinoma, Serous - drug therapy; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - metabolism; Cystadenocarcinoma, Serous - pathology; DNA damage repair; Drug Resistance, Neoplasm - genetics; FANCD2; Fanconi anaemia pathway; Fanconi Anemia Complementation Group D2 Protein - genetics; Fanconi Anemia Complementation Group D2 Protein - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Grading; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Platinum - pharmacology; Platinum - therapeutic use; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0014-4800; 1096-0945; 1096-0945
• DOI: 10.1016/j.yexmp.2024.104916

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of ovarian cancer and demonstrates 5-year survival of just 40%. One of the major causes of mortality is the development of tumour resistance to platinum-based chemotherapy, which can be modulated by dysregulation of DNA damage repair pathways. We therefore investigated the contribution of the DNA interstrand crosslink repair protein FANCD2 to chemosensitivity in HGSOC. Increased FANCD2 protein expression was observed in some cell line models of platinum resistant HGSOC compared with paired platinum sensitive models. Knockdown of FANCD2 in some cell lines, including the platinum resistant PEO4, led to increased carboplatin sensitivity. Investigation into mechanisms of FANCD2 regulation showed that increased FANCD2 expression in platinum resistant cells coincides with increased expression of mTOR. Treatment with mTOR inhibitors resulted in FANCD2 depletion, suggesting that mTOR can mediate platinum sensitivity via regulation of FANCD2. Tumours from a cohort of HGSOC patients showed varied nuclear and cytoplasmic FANCD2 expression, however this was not significantly associated with clinical characteristics. Knockout of FANCD2 was associated with increased cell migration, which may represent a non-canonical function of cytoplasmic FANCD2. We conclude that upregulation of FANCD2, possibly mediated by mTOR, is a potential mechanism of chemoresistance in HGSOC and modulation of FANCD2 expression can influence platinum sensitivity and other tumour cell characteristics. •Expression of FANCD2 is higher in some chemoresistant HGSOC cell lines than paired chemosensitive cell lines.•Knockdown of FANCD2 in some HGSOC cell lines can lead to increased chemosensitivity.•FANCD2 expression can be modulated by mTOR in HGSOC.•FANCD2 expression varies in HGSOC tumours, with both nuclear and cytoplasmic localization.•Knockout of FANCD2 can lead to increased cell migration.