Cancer upregulated gene 2, a novel oncogene, enhances migration and drug resistance of colon cancer cells via STAT1 activation

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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Identification of proteins associated to multi-drug resistance in LoVo human colon cancer cells

International Journal of Oncology ◽

10.3892/ijo_00000255 ◽

2009 ◽

Author(s):

Toffoli

Keyword(s):

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Human Colon ◽

Multi Drug Resistance ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Human Colon Cancer Cells

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miRNA-29a reverses P-glycoprotein-mediated drug resistance and inhibits proliferation via up-regulation of PTEN in colon cancer cells

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.173138 ◽

2020 ◽

Vol 880 ◽

pp. 173138 ◽

Cited By ~ 1

Author(s):

Xiaoxin Shi ◽

Amir Valizadeh ◽

Seyed Mostafa Mir ◽

Zatollah Asemi ◽

Ansar Karimian ◽

...

Keyword(s):

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Colon Cancer Cells ◽

P Glycoprotein

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GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells

Carcinogenesis ◽

10.1093/carcin/bgaa074 ◽

2020 ◽

Vol 41 (10) ◽

pp. 1329-1340 ◽

Cited By ~ 1

Author(s):

Ga-Bin Park ◽

Jee-Yeong Jeong ◽

Daejin Kim

Keyword(s):

Colon Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Cell Metabolism ◽

Enzyme Activation ◽

Migration And Invasion ◽

Drug Resistant ◽

Cancer Resistance ◽

Colon Cancer Cells ◽

Migratory Activity

Abstract In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.

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