Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway

Abstract

Antitumor activity of kaempferol has been studied in various tumor types, but its potency in esophagus squamous cell carcinoma is rarely known. Here, we reported the activity of kaempferol against esophagus squamous cell carcinoma as well as its antitumor mechanisms. Results of cell proliferation and colony formation assay showed that kaempferol substantially inhibited tumor cell proliferation and clone formation in vitro. Flow cytometric analysis demonstrated that tumor cells were induced G0/G1 phase arrest after kaempferol treatment, and the expression of protein involved in cell cycle regulation was dramatically changed. Except the potency on cell proliferation, we also discovered that kaempferol had a significant inhibitory effect against tumor glycolysis. With the downregulation of hexokinase-2, glucose uptake and lactate production in tumor cells were dramatically declined. Mechanism studies revealed kaempferol had a direct effect on epidermal growth factor receptor (EGFR) activity, and along with the inhibition of EGFR, its downstream signaling pathways were also markedly suppressed. Further investigations found that exogenous overexpression of EGFR in tumor cells substantially attenuated glycolysis suppression induced by kaempferol, which implied that EGFR also played an important role in kaempferol-mediated glycolysis inhibition. Finally, the antitumor activity of kaempferol was validated in xenograft model and kaempferol prominently restrained tumor growth in vivo. Meanwhile, dramatic decrease of EGFR activity and hexokinase-2 expression were observed in kaempferol-treated tumor tissue, which confirmed these findings in vitro. Briefly, these studies suggested that kaempferol, or its analogues, may serve as effective candidates for esophagus squamous cell carcinoma management.

Kaempferol – A dietary anticancer molecule with multiple mechanisms of action: Recent trends and advancements

“…4). Furthermore, results of these studies demonstrate that KMFdependent arrest of G0/G1 or G2/M transition is possibly due to inhibition of epidermal growth factor receptor (EGFR) activity, hexokinase-2 expression (Yao et al, 2016), inhibition of the activity of estrogen (Kim et al, 2016) or uptake of glucose (Azevedo et al, 2015). Of note, growth factors, hormones, glucose and hexokinases are positive regulators of cell cycle.…”

“…Recent in vitro and in vivo studies have shown the antiproliferative and proapoptotic activities of KMF against various types of cancers including breast (Azevedo et al, 2015;Kim, Hwang, & Choi, 2016;Liao et al, 2016), ovarian (Luo, Rankin, Li, Depriest, & Chen, 2011), lung (Kuo et al, 2015), pancreas (Zhang, Chen, Li, Chen, & Yao, 2008), esophagus (Yao et al, 2016), stomach , colon , prostate (Halimah et al, 2015), bladder (Dang et al, 2015), kidney (Song et al, 2014) and others. Most of these studies demonstrate that the mechanism of KMF is dependent on the inhibition of proliferation of various cancer cells either via cell cycle arrest or induction of apoptosis (Kuo et al, 2015;Liao et al, 2016).…”

“…including G0/G1 transition in esophagus squamous cell carcinoma (Yao et al, 2016) or G2/M transition in HT-29 human colon cancer cells . KMF additionally inhibits the expression of various cyclins like cyclin D1 and cyclin E in breast cancer cells (Kim et al, 2016), cyclin B1 in gastric cancer cells and renal cell carcinoma (Song et al, 2014 cyclin D, cyclin E and cyclin A in colon cancer cells and cyclin-dependent kinases like CDK4 and CDK2 .…”

Kaempferol Attenuates ROS-Induced Hemolysis and the Molecular Mechanism of Its Induction of Apoptosis on Bladder Cancer

“…Kaempferol ( Figure 1 ) is a flavonoid abundantly found in Psidium guajava , ginger, propolis and teas [ 3 , 4 , 5 ]. The anti-inflammation and anti-diabetic activity of kaempferol has gained much attention [ 6 , 7 ].…”

Butein Inhibited In Vitro Hexokinase-2-Mediated Tumor Glycolysis in Hepatocellular Carcinoma by Blocking Epidermal Growth Factor Receptor (EGFR)

“…HK-2 is considered to be the principal regulated isoform in different cell types [ 6 ]. The analysis of clinical specimens demonstrated that HK2 overexpression occurs in a variety of cancers, including breast cancer [ 7 ], gastric cancer [ 8 ], esophageal carcinoma [ 9 ], and cervical cancer [ 10 ]. In HCC, HK-2 was found to be overexpressed in 55.67% of clinical specimens and was closely correlated with the poor survival of patients [ 11 ].…”