FDFT1 Reduces Stemness and Autocrine/Juxtacrine Signaling in FOLFOX-resistant Colon Cancer Cells

Background: Colon cancer (CC) is a prevalent malignant tumor, that is widely treated with chemotherapy drug, such as 5fluorouracil+oxaliplatin (FOLFOX). However, the emergence of FOLFOX resistance poses a significant challenge to its therapeutic efficacy. This study aimed to investigate the effect of farnesyl-diphosphate farnesyltransferase (FDFT1) on the progression of FOLFOX-resistant CC cells. Methods: The human CC cells, including HCT-116 and HT-29, were used in establishing a chemotherapy-resistant cell model by their exposure to FOLFOX. Furthermore, these cells were transfected with either FDFT1-overexpression plasmid or empty vector. The impact of FDFT1 expression on the FOLFOX-resistant CC cells was evaluated by assessing the levels of cancer stem cell markers using real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blot analysis. Furthermore, the colony formation and the DNA damage/condensation were examined employing the colony forming assay and 4 ',6diamidino-2-phenylindole (DAPI) nuclei staining method, respectively. Moreover, western blot analysis was used to determine the levels of chemotherapy-resistance-related proteins, cell proliferation-related epidermal growth factor receptor (EGFR), and autocrine/juxtacrine pathway-related transforming growth factor alpha (TGF-alpha). Finally, the apoptosis rate in the transfected cells was assessed utilizing terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and flow cytometry. Results: The FDFT1 was downregulated in FOLFOX-resistant cells (p < 0.01) and cell transfection successfully upregulated FDFT1 in FOLFOX-resistant cells (p < 0.01). Furthermore, FDFT1 overexpression substantially reduced cancer stem cell markers (p < 0.01), inhibited tumor sphere formation (p < 0.01), increased DNA condensation (p < 0.001), and suppressed drug-related proteins (p < 0.001) in FOLFOX-resistant cells. Moreover, overexpression of FDFT1 suppressed the cell proliferation and reduced the activity of autocrine/juxtacrine signaling in FOLFOX-resistant cells by downregulating EGFR (p < 0.001) and TGF-alpha (p < 0.001). Additionally, FDFT1 increased apoptosis in FOLFOX-resistant cells when exposed to FOLFOX (p < 0.01). Conclusion: This study revealed an inhibitory role of FDFT1 in FOLFOX-resistant CC cells. Overexpression of FDFT1 can reduce cancer stem cell markers and inhibit tumor proliferation. Additionally, overexpression of FDFT1 suppressed the activity of autocrine/juxtacrine signaling, leading to increased cell apoptosis. These findings suggest FDFT1 as a potential therapeutic target and offer new insights for improving the efficacy of FOLFOX.