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Exploratory Proteomic Profiling Reveals Potential Mediators of 5-FU Response under p53 Deficiency in Colon Cancer
Seonyong Lee1,2, Jiwon Lee1, Ga Seul Lee3
1College of Pharmacy, Duksung Women's University, Seoul 01369, Republic of Korea.
Abstract:
Mutations in p53 have been implicated in poor prognosis and reduced sensitivity to 5-fluorouracil (5-FU) treatment in colon cancer. While p53-dependent mechanisms have been widely studies, less is known about how p53 deficiency reshapes cellular signaling and contributes to 5-FU resistance. In this study, we aimed to profile proteomic alterations associated with p53 loss by comparing colon cancer cells with and without p53 expression. Differentially expressed proteins (DEPs) related to cell cycle regulation were of particular interest, as 5-FU treatment induced G1 phase arrest in HCT116 p53 wild-type (WT) cells, whereas p53 knockout (KO) cells predominantly showed S phase arrest. We identified several DEPs in p53 deficient cells following 5-FU treatment. Notably, F3 expression was increased, while aldehyde dehydrogenase family 1 member A4 (ALDH1A3), histone deacetylase 2 (HDAC2), and protein S100-A4 (S100A4) were decreased. The expression levels of these genes were associated with overall survival in patients with colon cancer. These findings highlight proteomic alterations linked to p53 deficiency and support a proposed model in which differential regulation of specific proteins may be associated with reduced sensitivity to 5-FU, providing a basis for future mechanistic and functional studies.
Insights
Colon cancer cells lacking p53 show altered protein expression, contributing to resistance against 5-fluorouracil (5-FU) chemotherapy. Understanding these proteomic changes offers new insights into treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Proteomics
Background:
- p53 gene mutations are linked to poor prognosis and 5-fluorouracil (5-FU) resistance in colon cancer.
- p53's role in 5-FU resistance is not fully understood, especially regarding cellular signaling alterations.
Purpose of the Study:
- To profile proteomic changes in colon cancer cells with and without p53 expression after 5-FU treatment.
- To investigate how p53 deficiency impacts cellular signaling and contributes to 5-FU resistance.
Main Methods:
- Comparative proteomic analysis of colon cancer cells (HCT116 p53 wild-type vs. p53 knockout).
- Assessment of cell cycle arrest patterns (G1 vs. S phase) following 5-FU treatment.
- Identification of differentially expressed proteins (DEPs) in p53-deficient cells.
Main Results:
- p53 knockout cells exhibited S phase arrest, unlike wild-type cells showing G1 arrest upon 5-FU treatment.
- Key DEPs identified: increased F3 expression; decreased aldehyde dehydrogenase family 1 member A4 (ALDH1A3), histone deacetylase 2 (HDAC2), and protein S100-A4 (S100A4).
- Expression levels of these DEPs correlated with overall survival in colon cancer patients.
Conclusions:
- p53 deficiency leads to specific proteomic alterations in colon cancer cells.
- Differential protein regulation associated with p53 loss may contribute to reduced 5-FU sensitivity.
- Findings provide a foundation for further research into mechanisms of 5-FU resistance in p53-deficient colon cancer.
