Abstract
The phosphorylation of pyruvate dehydrogenase (PDH) by pyruvate dehydrogenase kinase (PDK) 4 inhibits its ability to induce a glycolytic shift. PDK4 expression is upregulated in various types of human cancer. Because PDK4 regulation is critical for metabolic changes in cancer cells, it is an attractive target for cancer therapy given its ability to shift glucose metabolism. It was previously shown that a novel PDK4 inhibitor, cryptotanshinone (CPT), suppressed the three-dimensional (3D)-spheroid formation of pancreatic and colorectal cancer cells. In the present study, the effects of CPT on the invasiveness of bladder cancer cells were investigated. CPT significantly suppressed the invasiveness and 3D-spheroid formation of T24 and J82 bladder cancer cells. CPT also suppressed the phosphorylation of PDH and β-catenin, as well as the expression of N-cadherin, which are all critical for inducing epithelial-mesenchymal transition (EMT). The knockdown of β-catenin or PDK4 using specific small interfering RNAs suppressed N-cadherin expression and invasiveness in T24 cells. An mTOR inhibitor also suppressed the phosphorylation of β-catenin and N-cadherin expression. Furthermore, CPT injection significantly suppressed pancreatic tumor growth and peritoneal dissemination of highly metastatic SUIT-2 pancreatic cancer cells in a mouse orthotopic pancreatic cancer model, without evident toxicity. Moreover, immunohistochemistry analyses demonstrated decreased β-catenin expression in CPT-treated pancreatic tumors compared with control tumors. Taken together, these results indicate that CPT reduced the invasiveness and metastasis of bladder cancer cells by suppressing EMT via the mTOR/β-catenin/N-cadherin pathway.
Highlights
Under aerobic conditions, the majority of proliferating cancer cells preferentially metabolize glucose via glycolysis, which is a primary metabolic hallmark of cancer cells [1,2,3]
Immunohistochemistry analyses demonstrated decreased β‐catenin expression in CPT‐treated pancreatic tumors compared with control tumors. These results indicate that CPT reduced the invasive‐ ness and metastasis of bladder cancer cells by suppressing epithelial‐mesenchymal transi‐ tion (EMT) via the mTOR/β‐catenin/N‐cadherin pathway
The expression levels of pyruvate dehydroge‐ nase (PDH) and α‐tubulin remained unaffected by CPT treatment, while PDK4 expression was suppressed by 20 μM CPT
Summary
The majority of proliferating cancer cells preferentially metabolize glucose via glycolysis, which is a primary metabolic hallmark of cancer cells [1,2,3]. The inhibition of PDKs can restimulate the mitochondria metabolism of pyruvate in cancer cells [5], which subsequently inhibits tumor growth [6]. Trinidad et al [9] reported that PDK4‐knockdown using specific small interfering (si)RNAs suppressed lung and colorectal cancer cell proliferation, which suggests that PDK4 is an attractive target for cancer therapy. Our previous study demonstrated that cryptotanshinone (CPT), which is obtained from the traditional Chinese herb Salvia miltiorrhiza Bunge (danshen), effectively inhibited PDK4 activity at low concentrations (micromolar‐order) to suppress malignant phenotypes, including three‐dimensional (3D)‐spheroid formation, anchorage‐independent growth, KIM et al: SUPPRESSION OF INVASIVENESS BY CRYPTOTANSHINONE IN BLADDER CANCER VIA β-CATENIN cellular proliferation and in vivo tumor growth of human pancreatic and colorectal cancer [15]
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