Abstract 5709: Furin drives colorectal cancer progression and chemoresistance through the TGF-β/ERK signaling pathway

Abstract Furin, a key member of the pro-protein convertase (PC) family, is unfavorably involved in the proteolytic activation of various precursor proteins. While aberrant expression of furin has been extensively documented in multiple malignancies, its functional significance and mechanistic role in colorectal cancer remain inadequately characterized. We analyzed furin expression in a comprehensive cohort of Middle Eastern colorectal cancer (CRC) patient samples and investigated its functional role and underlying mechanisms using in vitro studies with CRC cell lines. Furin over-expression was noted in 46.9% (530/1131) of CRC cases. A significant association was noted between Furin over-expression and older age at diagnosis of CRC (>50 years; p = 0.0156), but no significant association was noted with other clinico-pathological characteristics. However, Furin over-expression was found to be associated with phosphor-ERK1/2 (p < 0.0001) and TGFβ (p < 0.0001). For in vitro analysis, we selected three chemosensitive CRC cell lines—HCT116, DLD1, and LOVO—and generated chemoresistant cells by treating them to prolonged low-dose 5-fluorouracil (5-FU). Our results revealed that 5-FU-resistant CRC cell lines exhibited elevated furin expression, accompanied by increased levels of TGF-β protein and phosphorylated ERK1/2 (pERK1/2). Notably, furin knockdown restored chemosensitivity, highlighting its critical role in drug resistance. Furthermore, we demonstrated that TGF-β treatment upregulated furin and pERK1/2 expression, while forced furin overexpression similarly induced TGF-β and pERK1/2 expression. Collectively, these findings suggest that furin plays a pivotal role in CRC progression and chemoresistance by activating the TGF-β/ERK signaling pathway. Citation Format: Abdul K. Siraj, Pratheesh Kumar Poyil, Sandeep Kumar Parvathareddy, Saravanan Thangavel, Fouad Al-Dayel, Khawla S. Al-Kuraya. Furin drives colorectal cancer progression and chemoresistance through the TGF-β/ERK signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5709.