Cryptotanshinone, a novel PDK 4 inhibitor, suppresses bladder cancer cell invasiveness via the mTOR/β‑catenin/N‑cadherin axis

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.

Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

“…Furthermore, GO and KEGG enrichment analysis revealed that PDK1-3 was correlational with the critical biological process involved in tumorigenesis, including nucleotide excision repair, DNA replication, RNA splicing, etc., presenting PDK1-3 as potential therapeutic targets for BCa. However, the decreased expression levels of PDK4 in the mixed and glycolytic subtypes did not match our inferences and was inconsistent with other reports [ 56 , 57 ]. Further studies are needed to investigate the roles played by PDKs in BCa development.…”

“…Thus, inhibition of PDK has been recognized as an attractive strategy in anticancer therapy [ 54 , 55 ]. While the roles and mechanisms of PDK1-3 in BCa remain unknown, enhanced PDK4 expression in BCa has been reported in previous studies, and PDK4 inhibitors were found to suppress BCa cell invasiveness and to potentiate cisplatin-induced cell death [ 56 , 57 ]. In this study, we observed significantly lower PDK1-3 expression levels in the quiescent subtype as compared to the other subtypes, consistent with the notion that PDKs contribute to tumorigenesis by inhibiting PDC activity [ 54 , 55 ].…”

Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells

“…This process is detrimental to cancer cells and suppresses 3D-spheroid formation in malignant pancreatic cancer cells containing mutant KRAS. Previously, we showed that CPT suppresses cancer cell invasiveness and metastasis in a mouse model ( 28 ). Thus, CPT is expected to be a potent therapeutic drug for KRAS-driven intractable cancers.…”

Diagnostic genes and immune infiltration analysis of colorectal cancer determined by LASSO and SVM machine learning methods: a bioinformatics analysis

“…Pyruvate Dehydrogenase Kinase (PDK) generates four kinase families in humans. PDK4 is mainly expressed in muscle and affects glucose consumption during metabolism (53). It has been reported in the literature that when PDK4 was stably inhibited, colorectal cancer cell migration and invasion were reduced, and apoptosis was increased.…”