Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells.
BACKGROUND
Accumulating preclinical and clinical evidence implicates epithelial-mesenchymal transition (EMT) in acquired resistance to anticancer drugs; however, mechanisms by which the mesenchymal state determines drug resistance remain unknown.


RESULTS
To explore a potential role for altered cellular metabolism in EMT and associated drug resistance, we analyzed the metabolome and transcriptome of three lung cancer cell lines that were rendered drug resistant following experimental induction of EMT. This analysis revealed evidence of metabolic rewiring during EMT that diverts glucose to the TCA cycle. Such rewiring was at least partially mediated by the reduced expression of pyruvate dehydrogenase kinase 4 (PDK4), which serves as a gatekeeper of the TCA cycle by inactivating pyruvate dehydrogenase (PDH). Overexpression of PDK4 partially blocked TGFβ-induced EMT; conversely, PDK4 inhibition via RNAi-mediated knockdown was sufficient to drive EMT and promoted erlotinib resistance in EGFR mutant lung cancer cells. We identified a novel interaction between PDK4 and apoptosis-inducing factor (AIF), an inner mitochondrial protein that appears to play a role in mediating this resistance. In addition, analysis of human tumor samples revealed PDK4-low as a predictor of poor prognosis in lung cancer and that PDK4 expression is dramatically downregulated in most tumor types.


CONCLUSIONS
Together, these findings implicate PDK4 as a critical metabolic regulator of EMT and associated drug resistance.
Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Yuting
Y
Sun
Department of Bioinformatics, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Anneleen
A
Daemen
Department of Translational Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Georgia
G
Hatzivassiliou
Department of Protein Chemistry, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
David
D
Arnott
Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Catherine
C
Wilson
Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Guanglei
G
Zhuang
Department of Translational Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Min
M
Gao
Department of Protein Chemistry, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Peter
P
Liu
Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Aaron
A
Boudreau
Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Leisa
L
Johnson
Department of Discovery Oncology, Genentech Inc, 1 DNA Way, 94080 South San Francisco, CA USA.
Jeff
J
Settleman
Drug resistance; EMT; Pyruvate dehydrogenase kinase; Tumor metabolism