Forkhead box O3 promotes colon cancer proliferation and drug resistance by activating MDR1 expression

Drug resistance is one of the main causes of colon cancer recurrence. However, our understanding of the underlying mechanisms and availability of therapeutic options remains limited. Here we show that expression of pyruvate dehydrogenase kinase 4 (PDK4) is positively correlated with drug resistance of colon cancer cells and induced by 5-fluorouracil (5-FU) treatment in drug-resistant but not drug-sensitive cells. Knockdown of PDK4 expression sensitizes colon cancer cells to 5-FU or oxaliplatin-induced apoptosis in vitro and increases the effectiveness of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. In addition, we demonstrate for the first time that TGFβ mediates drug resistance by regulating PDK4 expression and that 5-FU induces PDK4 expression in a TGFβ signaling-dependent manner. Mechanistically, knockdown or inhibition of PDK4 significantly increases the inhibitory effect of 5-FU on expression of the anti-apoptotic factors Bcl-2 and survivin. Importantly, studies of patient samples indicate that expression of PDK4 and phosphorylation of Smad2, an indicator of TGFβ pathway activation, show a strong correlation and that both positively associate with chemoresistance in colorectal cancer. These findings indicate that the TGFβ/PDK4 signaling axis plays an important role in the response of colorectal cancer to chemotherapy. A major implication of our studies is that inhibition of PDK4 may have considerable therapeutic potential to overcome drug resistance in colorectal cancer patients, which warrants the development of PDK4-specific inhibitors.

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Impedance-based drug-resistance characterization of colon cancer cells through real-time cell culture monitoring

Talanta ◽

10.1016/j.talanta.2020.121441 ◽

2021 ◽

Vol 222 ◽

pp. 121441

Author(s):

Fuentes-Vélez Susana ◽

Fagoonee Sharmila ◽

Sanginario Alessandro ◽

Gallo Valentina ◽

Riganti Chiara ◽

...

Keyword(s):

Cell Culture ◽

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Real Time ◽

Colon Cancer Cells ◽

Culture Monitoring

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Knockdown of Forkhead box A1 suppresses the tumorigenesis and progression of human colon cancer cells through regulating the phosphatase and tensin homolog/Akt pathway

Journal of International Medical Research ◽

10.1177/0300060520971453 ◽

2020 ◽

Vol 48 (12) ◽

pp. 030006052097145

Author(s):

Jie Pan ◽

Zongbin Xu ◽

Meifang Xu ◽

Xiaoyan Lin ◽

Bingqiang Lin ◽

...

Keyword(s):

Colon Cancer ◽

Human Colon ◽

Migration And Invasion ◽

Human Colon Cancer ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Forkhead Box ◽

Mrna And Protein Expression ◽

Cancer Tissues ◽

Foxa1 Expression

Background This study aimed to evaluate the role and the underlying mechanisms of Forkhead box A1 (encoded by FOXA1) in colon cancer. Methods We analyzed FOXA1 mRNA and protein expression in colon cancer tissues and cell lines. We also silenced FOXA1 expression in HCT116 and SW480 cells to evaluate the effects on cell proliferation, cell cycle, migration, and invasion by using MTT, colony formation, flow cytometry, and the Transwell assay, respectively. Results FOXA1 immunostaining was higher in colon cancer tissues than adjacent healthy tissues. FOXA1 mRNA and protein expression was significantly increased in human colon cancer cells compared with a normal colonic cell line. FOXA1 expression was also significantly higher in colorectal cancer tissues from TCGA data sets and was associated with worse prognosis in the R2 database. FOXA1 expression was negatively correlated with the extent of its methylation, and its knockdown reduced proliferation, migration, and invasion, and induced G2/M phase arrest in HCT116 and SW480 cells by suppressing the phosphatase and tensin homolog/Akt signaling pathway and inhibiting epithelial–mesenchymal transition. Conclusion FOXA1 may act as an oncogene in colon cancer tumorigenesis and development.

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