Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling

Abstract

Background Kaempferol, a natural flavonoid, exhibits anticancer properties by scavenging reactive oxygen species (ROS). However, increasing evidence has demonstrated that, under certain conditions, kaempferol can inhibit tumor growth by upregulating ROS levels. In this study, we aimed to investigate whether kaempferol effectively suppresses pancreatic cancer through upregulation of ROS, and to explore the underlying molecular mechanism. Methods PANC-1 and Mia PaCa-2 cells were exposed to different concentrations of kaempferol. Cell proliferation and colony formation were evaluated by CCK-8 and colony formation assays. Flow cytometry was performed to assess the ROS levels and cell apoptosis. The mRNA sequencing and KEGG enrichment analysis were performed to identify differentially expressed genes and to reveal significantly enriched signaling pathways in response to kaempferol treatment. Based on biological analysis, we hypothesized that tissue transglutaminase (TGM2) gene was an essential target for kaempferol to induce ROS-related apoptosis in pancreatic cancer. TGM2 was overexpressed by lentivirus vector to verify the effect of TGM2 on the ROS-associated apoptotic signaling pathway. Western blot and qRT-PCR were used to determine the protein and mRNA levels, respectively. The prognostic value of TGM2 was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) tools based on public data from the TCGA database. Results Kaempferol effectively suppressed pancreatic cancer in vitro and in vivo. Kaempferol promoted apoptosis in vitro by increasing ROS generation, which was involved in Akt/mTOR signaling. TGM2 levels were significantly increased in PDAC tissues compared with normal tissues, and high TGM2 expression was positively correlated with poor prognosis in pancreatic cancer patients. Decreased TGM2 mRNA and protein levels were observed in the cells after treatment with kaempferol. Additionally, TGM2 overexpression downregulated ROS production and inhibited the abovementioned apoptotic signaling pathway. Conclusions Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling, and TGM2 may represent a promising prognostic biomarker for pancreatic cancer.

Kaempferol Ameliorates the Inhibitory Activity of Dexamethasone in the Osteogenesis of MC3T3-E1 Cells by JNK and p38-MAPK Pathways

“…Kaempferol, a kind of flavonol and polyphenol antioxidant, has been found in many plants, including tea, apples, and beans and used for treating tumors and inflammatory diseases (Chen and Chen, 2013;Song et al, 2015;Molitorisova et al, 2021;Wang et al, 2021). Studies also demonstrated that kaempferol could stimulate osteogenic differentiation of mesenchymal stem cells (MSC) and osteoblasts (Yang et al, 2010;Byun et al, 2012;Kim et al, 2016;Adhikary et al, 2018).…”

Role of TGM2 in T‑cell lymphoblastic lymphoma via regulation of IL‑6/JAK/STAT3 signalling

“…In a previous study, inhibition of TGM2 suppressed docetaxel resistance and epithelial-to-mesenchymal transition in breast cancer ( 29 ). Furthermore, kaempferol has been reported to promote reactive oxygen species-related apoptosis via the TGM2-regulated Akt/mTOR pathway in pancreatic cancer cells ( 30 ). TGM2 was also revealed to be correlated with the prognosis of CRC and may serve as a potential treatment target ( 31 ).…”

Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma

“…Researchers have indicated the antioxidant potential of kaempferol in both in vitro and in vivo models [ 78 ]. It causes the scavenging of the free radicals and other ROS molecules, as their generation transforms the normal cells into malignant ones [ 79 ]. So, inhibition of these species alters the tumor cell phenotype.…”