Serum pyruvate dehydrogenase kinase as a prognostic marker for cholangiocarcinoma

Abstract

Pyruvate dehydrogenase kinase (PDK) is a Ser/Thr kinase that inactivates mitochondrial pyruvate dehydrogenase and serves a key role in aerobic glycolysis, which is a hallmark of cancer cells. The present study determined the PDK expression in cholangiocarcinoma (CCA) tissues and sera to evaluate their applicability as a biomarker for CCA. Using proteomic analysis, PDK was revealed to be the most overexpressed mitochondrial protein in CCA tissues. Then, the expression of PDK isoforms in CCA tissues was examined in 15 CCA cases by immunohistochemistry. The PDK3 isoform levels in the sera were measured using a dot blot assay for 39 patients with CCA, 20 patients with benign biliary disease and 19 healthy volunteers. The results revealed a 27-fold overexpression of PDK3 in cancerous tissues when compared with adjacent non-cancerous tissues. The immunohistochemical results demonstrated that the PDK1, 2 and 3, but not the PDK4, isoforms were overexpressed in cancerous tissues. When the PDK3 levels in the sera were examined, they were significantly higher in CCA when compared with the BBD and healthy groups. The specificity and sensitivity of PDK3 as a marker for CCA were 97.5 and 33.0%, respectively, and high PDK3 levels in the sera were correlated with a short survival time for CCA. In conclusion, PDK3 can be used as a diagnostic/prognostic marker for CCA.

Multifaceted Aspects of Metabolic Plasticity in Human Cholangiocarcinoma: An Overview of Current Perspectives

“…Moreover, PDK3 expression levels were considerably higher in CCA sera compared with the benign biliary diseases and healthy groups. In agreement, PDK3 levels correlated with a short survival time in CCA [37]. Overall, these data suggest that inhibition of mitochondrial metabolism and hence the sustenance of the glycolytic flux can be fundamental in CCA growth.…”

“…Other studies support the up-regulation of Warburg metabolism in CCA: pyruvate dehydrogenase kinases (PDKs) are Ser/Thr kinases that phosphorylate/inactivate mitochondrial pyruvate dehydrogenase, thus decreasing the oxidation of pyruvate in the tricarboxylic acid (TCA) cycle and increasing the Warburg effect [70]. Sanmai S. et al, [37] demonstrated that PDK1, PDK2 and PDK3, were significantly overexpressed in 15 CCA tissues compare to normal ones. Moreover, PDK3 expression levels were considerably higher in CCA sera compared with the benign biliary diseases and healthy groups.…”

“…PDK1 expression promotes glycolysis and CCA cell proliferation. [37] SIRT3 effects mediated by HIF1α/ PDK1/PDHA1 pathway Decrease of SIRT3 expression induced the glycolytic flux through the hypoxia inducible factor α (HIF1α)/PDK1/ PDHA1 axis, promoting CCA progression. [38] Deregulation of PI3K-AKT-mTOR signaling Protein overexpression and activation of PI3K have been associated with tumor progression, differentiation, nodal involvement and reduced OS.…”

Apoptosis-Inducing Factor, Mitochondrion-Associated 3 (AIFM3) Protein Level in the Sera as a Prognostic Marker of Cholangiocarcinoma Patients

“…Apart from AIFM3, several mitochondrial proteins such as mitochondrial ribosomal protein, mitochondrial stress 70 protein (mortalin), pyruvate dehydrogenase kinase 3, and manganese superoxide dismutase have been detected in the serum, and has been used as serum marker for breast cancer, colorectal cancer, CCA, and ovarian cancer [ 20 , 21 , 22 , 23 ] The present results suggest that AIFM3 should be added as a mitochondrial protein marker in the sera of patients with CCA and probably other cancers. In the present study, serum AIFM3 level in the CCA patients group was significantly ( p < 0.0001) higher than that of HC.…”

Role of Glucose Metabolism Reprogramming in the Pathogenesis of Cholangiocarcinoma

“…HIF1α is an important enzyme for metabolic adjustment during hypoxia and is involved in cancer cell survival, angiogenesis, and metastasis (28,37,57). CCA patients showed a higher level of Pyruvate dehydrogenase kinase 1 (PDK1) (58), which has been known to control the metabolic shift during hypoxia via regulating the acetyl-coA production to yield energy in the TCA cycle by mitochondria oxidation (59,60). The mTOR pathway regulates energy homeostasis and engages in cancer cell survival in cellular metabolic stress such as depletion in nutrients and energy (23,24).…”