PDK1- and PDK2-mediated metabolic reprogramming contributes to the TGFβ1-promoted stem-like properties in head and neck cancer

Abstract

Background Resistance to chemotherapeutic drugs is a key factor for cancer recurrence and metastases in head and neck cancer (HNC). Cancer stem cells (CSCs) in tumors have self-renewal, differentiation, and higher drug resistance capabilities, resulting in a poor prognosis for patients. In glucose metabolism, pyruvate dehydrogenase kinase (PDK) inhibits pyruvate dehydrogenase and impedes pyruvate from being metabolized into acetyl-CoA and entering the tricarboxylic acid cycle to generate energy. Studies have reported that PDK1 and PDK2 inhibition suppresses the growth, motility, and drug resistance of cancer cells. Furthermore, while TGFβ1 levels are persistently elevated in HNC patients with poor prognosis, the role of PDK isoforms in the TGFβ1-promoted progression and stem-like properties of HNC is unclear. Methods Levels of PDK1 and PDK2 were evaluated in HNC tissue microarrays by immunohistochemistry to explore potential clinical relevance. PDK1 and PDK2 were knocked down by the lentivirus shRNA system to investigate their role in TGFβ1-promoted tumor progression in vitro. Results We found that PDK2 levels were increased in the later stage of HNC tissues compared to constant PDK1 expression. After PDK1 and PDK2 knockdown, we discovered increased ATP production and decreased lactate production in TGFβ1-treated and untreated HNC cells. However, only PDK2 silencing significantly inhibited the clonogenic ability of HNC cells. We subsequently found that TGFβ1-promoted migration and invasion capabilities were decreased in PDK1 and PDK2 knockdown cells. The tumor spheroid-forming capability, motility, CSC genes, and multidrug-resistant genes were downregulated in PDK1 and PDK2 silencing CSCs. PDK1 and PDK2 inhibition reversed cisplatin and gemcitabine resistance of CSCs, but not paclitaxel resistance. Conclusion The results demonstrated that the PDK1- and PDK2-mediated Warburg effect contributes to the TGFβ1-enhanced stemness properties of HNC. Therefore, PDK1 and PDK2 may serve as molecular targets for the combination therapy of HNC.

Mitochondrial-related genes PDK2, CHDH, and ALDH5A1 served as a diagnostic signature and correlated with immune cell infiltration in ulcerative colitis

“…Specifically, PDK2 phosphorylates and inactivates PDH, a key enzyme that converts pyruvate into acetyl-CoA to enter the citric acid cycle and generate ATP in the mitochondria [ 19 ]. Growing evidence suggests that PDK2 influences glucose metabolism which is consequently attributed to tumor development [ 20 , 21 ]. Sachiko et al found that high PDK2 expression was associated with a poor prognosis and that inhibiting PDK2 increased cisplatin sensitivity by activating the electron transport chain and increasing the generation of mitochondrial reactive oxygen species in Ovarian clear cell carcinoma [ 22 ].…”

Enhancing oxidative phosphorylation through pyruvate dehydrogenase kinase 2 deficiency ameliorates cartilage degradation in surgically induced osteoarthritis

“…On the other hand, a decreasing energy charge and increasing pyruvate concentrations inhibit PDK activity, thereby leading to increased PDH activation (31). Although several mechanisms, including lactate dehydrogenase-A (LDH-A), hypoxiainducible factor 1A (HIF1A), the AKT-mTOR signaling pathway, and pyruvate kinase M2, are known to control the glycolytic shift in chondrocytes (8, 32-34), PDK is known to mediate the Warburg effectcharacterized by enhanced aerobic glycolysis (35). It may directly lead to the glycolytic shift observed in OA.…”

Pyruvate dehydrogenase kinase regulates macrophage polarization in metabolic and inflammatory diseases

“…Macrophages play different roles in pathogen-induced immune responses, tissue repair, and maintenance of homeostasis. Thus, regulating PDK2 to alter macrophage metabolism and influence their activation or polarization has considerable therapeutic potential in cancer and inflammatory diseases ( 37 , 51 – 53 ). The B7 family co-stimulatory molecule V-set and immunoglobulin domain-containing 4 (VSIG4) are complementary receptors of the immunoglobulin superfamily that are macrophage-specific surface molecules.…”