Fisetin inhibits the proliferation, migration and invasion of pancreatic cancer by targeting PI3K/AKT/mTOR signaling

Abstract

Pancreatic cancer is an extremely malignant digestive tract tumor. With the increase of chemotherapeutic resistance of pancreatic cancer, clinical treatment is in a dilemma. Hence, it is pivotal to design an effective drug for treating individuals with pancreatic cancer. Fisetin extracted from vegetables, as well as fruits was explored to possess antioxidant, anti-cancer, anti-inflammatory along with anti-microbial properties. Nonetheless, there is limited research focusing on the utility of fisetin as an inhibitor of pancreatic cancer. Similarly, the mechanism through which Fisetin dampens pancreatic cancer remains unknown. This research work systematically evaluated the possible anti-cancer influences of fisetin in pancreatic cancer, as well as explored its responsible molecular mechanism. Our data revealed that fisetin obviously dampens pancreatic cancer progress in vitro along with in vivo dose-dependently. Furthermore, we established that fisetin repressed pancreatic cancer via explicitly targeting PI3K/AKT/mTOR signaling cascade and not the JAK2 cascade. Our data clarified that fisetin is a prospective anti-cancer drug for pancreatic cancer, as well as indicated the distinct molecular target of fisetin.

Fisetin, a Potent Anticancer Flavonol Exhibiting Cytotoxic Activity against Neoplastic Malignant Cells and Cancerous Conditions: A Scoping, Comprehensive Review

“…Moreover, total mTOR is not changed; nevertheless, p-mTOR and PI3K are significantly decreased, indicating that the PI3K/AKT/mTOR cascade is involved in the inhibition of FIS-treated cells. This suggests that FIS may inhibit growth, invasion and migration by suppressing the PI3K/AKT/mTOR cascade [5,111]. FIS also causes IK-Kα/β inhibition, phosphorylation and degradation of IκBα, and subsequent activation of NF-κB [111].…”

“…FIS does not reduce the content of vimentin; however, it significantly increases the content of the epithelial marker E-cadherin and weakens the content of the interstitial markers N-cadherin and a-SMA, which results in a reduction in the extracellular matrix (ECM) secreted by stromal tumor cells [5].…”

“…FIS activates apoptosis [123] and causes a strong increase in caspase-3 and -8 activation and an increase in PARP cleavage, indicating that it promotes cell apoptosis through a mitochondrial-dependent cascade [5,111]. In addition, the death domain containing TNFR1 and TNFRSF25 (DR3) receptors shows a strong modulation after FIS treatment.…”

“…The hidden potential and magnitude of natural compounds against cancer cells is yet to be discovered, based on robust and well-designed studies with replicable results. Interestingly, it is worth noticing that many current first-line anticancer drugs such as paclitaxel and colchicine originate from natural products [5,6].…”

Antiangiogenic Phytochemicals Constituent of Diet as Promising Candidates for Chemoprevention of Cancer

“…The chemotherapeutic potential of fisetin in cancer and its multi-target mechanism of action leading to cell cycle arrest, apoptosis, and autophagic cell death have been reported in numerous in vitro and in vivo works [ 31 , 104 , 105 , 106 , 107 ]. Interestingly, this antioxidant flavonol shows antiangiogenic activity in vitro and in vivo, inhibiting endothelial survival, proliferation, migration, and tube formation [ 108 , 109 ] ( Table 1 ).…”