Abstract
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.
Highlights
PDK4 expression and that 5-FU induces PDK4 expression in a tify new targets to increase the effectiveness of chemotherapy in
A major implication of our studies is studies have shown that TGF promotes metastasis [7], others that inhibition of PDK4 may have considerable therapeutic have demonstrated that TGF suppresses metastasis [8, 9]. potential to overcome drug resistance in colorectal cancer Recently, studies have indicated that TGF signaling is an patients, which warrants the development of PDK4-specific emerging player in cancer drug resistance (10 –12)
Expression of PDK4 Positively Correlates with 5-FU Resistance in Colon Cancer Cells—To understand the mechanisms and identify the determinants underlying drug resistance, we examined a panel of colon cancer cell lines for their response to 5-FU treatment
Summary
University of Nebraska Medical Center, 985950 Nebraska Medical vate dehydrogenase; PDK, pyruvate dehydrogenase kinase; DCA, dichlo-. TGF/PDK4 Confers Drug Resistance cycle, representing a key regulatory step in glucose metabolism. We have identified a novel function of PDK4 that mediates the response of colon cancer cells to 5-FU treatment. We show that PDK4, but not PDK1–3, is differentially expressed in colon cancer cells and that its expression positively correlates with the resistance to 5-FU treatment. Knockdown of PDK4 sensitizes colon cancer cells to 5-FU- or oxaliplatin-induced apoptosis. TGF signaling enhances PDK4 expression, and elevated PDK4 expression contributes to TGF-mediated drug resistance in colon cancer cells. Studies of patient specimens show that PDK4 expression and TGF activation positively correlate with each other and with chemoresistance in colorectal cancer, indicating the clinical relevance of our studies. Our studies unveil a novel function of TGF/PDK4 in mediating drug resistance in colorectal cancer
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