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

Abstract

Pyruvate dehydrogenase kinase 4 (PDK4) is an important regulator of energy metabolism. Previously, knockdown of PDK4 by specific small interfering RNAs (siRNAs) have been shown to suppress the expression of Κirsten rat sarcoma viral oncogene homolog (KRAS) and the growth of lung and colorectal cancer cells, indicating that PDK4 is an attractive target of cancer therapy by altering energy metabolism. The authors previously reported that a novel small molecule, cryptotanshinone (CPT), which inhibits PDK4 activity, suppresses the in vitro three-dimensional (3D)-spheroid formation and in vivo tumorigenesis of KRAS-activated human pancreatic and colorectal cancer cells. The present study investigated the molecular mechanism of CPT-induced tumor suppression via alteration of glutamine and lipid metabolism in human pancreatic and colon cancer cell lines with mutant and wild-type KRAS. The antitumor effect of CPT was more pronounced in the cancer cells containing mutant KRAS compared with those containing wild-type KRAS. CPT treatment decreased glutamine and lipid metabolism, affected redox regulation and increased reactive oxygen species (ROS) production in the pancreatic cancer cell line MIAPaCa-2 containing mutant KRAS. Suppression of activated KRAS by specific siRNAs decreased 3D-spheroid formation, the expression of acetyl-CoA carboxylase 1 and fatty acid synthase (FASN) and lipid synthesis. The suppression also reduced glutathione-SH/glutathione disulfide and increased the production of ROS. Knockdown of FASN suppressed lipid synthesis in MIAPaCa-2 cells, partially promoted ROS production and mildly suppressed 3D-spheroid formation. These results indicated that CPT reduced tumorigenesis by inhibiting lipid metabolism and promoting ROS production in a mutant KRAS-dependent manner. This PDK4 inhibitor could serve as a novel therapeutic drug for KRAS-driven intractable cancers via alteration of cell metabolism.

Genetic Ablation of Pyruvate Dehydrogenase Kinase Isoform 4 Gene Enhances Recovery from Hyperoxic Lung Injury: Insights into Antioxidant and Inflammatory Mechanisms

“…Given the frequent upregulation of PDK4 in various cancers, ongoing drug research involves investigations involving Cryptotanshinone as a PDK4 inhibitor [35,36]. Studies have shown that Cryptotanshinone not only impedes the progression of pulmonary fibrosis [37] but may also have a potential therapeutic effect in interstitial lung disease [38].…”

The role of metabolic reprogramming in pancreatic cancer chemoresistance

“…A recent study showed that KRAS also promotes fatty acid synthesis and energy metabolism by upregulating the expression of phospholipase A2 group IIA, which may be a new therapeutic target as a KRAS downstream molecule ( Zhang et al, 2022 ). Targeting pyruvate dehydrogenase kinase 4 in glucose metabolism also interferes with lipid metabolism and promotes ROS production, thereby reducing the proliferation of KRAS mutation-driven PC cells ( Terado et al, 2022 ). In addition, CDK4/6 inhibitors target miR-33a to regulate AMPK/mTOR signaling and downregulate fatty acid anabolism ( Rencuzogulları et al, 2022 ).…”

Targeting dysregulated lipid metabolism in the tumor microenvironment

“…Moreover, mutant K-Ras has been shown to stimulate lipogenesis by controlling lipogenic enzymes, including ACC1 and FASN (Kerk et al 2021 ). Knockdown of K-Ras suppresses the levels of ACC1 and FASN expression, contributing to the suppression of spheroid formation through ROS production in K-Ras-activated pancreatic cancer cells (Terado et al 2022 ).…”