Fisetin induces G2/M phase arrest and caspase‐mediated cleavage of p21Cip1 and p27Kip1 leading to apoptosis and tumor growth inhibition in HNSCC

The anticancer potential and associated mechanisms of flavonoid fisetin are yet to be fully investigated on human head and neck squamous cell carcinoma (HNSCC). In the present study, fisetin (25‐75 µM for 24–48 h) dose‐dependently inhibited growth and induced death in HNSCC Cal33 and UM‐SCC‐22B cell...

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Published in:Molecular carcinogenesis 2024-09, Vol.63 (9), p.1697-1711
Main Authors: Yadav, Monika, Kandhari, Kushal, Mathan, Sivapar V., Ali, Mansoor, Singh, Rana P.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Apoptosis
Autophagy
Body weight
Cancer
Caspase
Caspase inhibitors
Cell activation
Cell death
Comet assay
Cyclin B1
Cyclin-dependent kinase inhibitor p21
Cyclin-dependent kinase inhibitor p27
DNA damage
EGFR‐Akt/ERK1/2‐STAT‐3
Epidermal growth factor receptors
Extracellular signal-regulated kinase
fisetin
Flavonoids
Gene expression
GTP-binding protein
Head & neck cancer
Head and neck carcinoma
HNSCC
JNK signaling
p21Cip1
p53 Protein
Phosphorylation
Reactive oxygen species
Squamous cell carcinoma
Tumors
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Summary:The anticancer potential and associated mechanisms of flavonoid fisetin are yet to be fully investigated on human head and neck squamous cell carcinoma (HNSCC). In the present study, fisetin (25‐75 µM for 24–48 h) dose‐dependently inhibited growth and induced death in HNSCC Cal33 and UM‐SCC‐22B cells, without showing any death in normal cells. Fisetin (25–50 µM) induced G2/M phase arrest via decrease in Cdc25C, CDK1, cyclin B1 expression, and an increase in p53(S15). A concentration‐dependent increase in fisetin‐induced DNA damage and apoptosis in HNSCC cells was authenticated by comet assay, gamma‐H2A.X(S139) phosphorylation, and marked cleavage of PARP protein. Interestingly, fisetin‐induced cell death occurred independently of p53 and reactive oxygen species production. The activation of JNK and inhibition of PI3K/Akt, ERK1/2, EGFR, and STAT‐3 signaling were identified. Further, fisetin‐induced apoptosis was mediated, in part, via p21Cip1 and p27Kip1 cleavage by caspase, which was reversed by z‐VAD‐FMK, a pan‐caspase inhibitor. Subsequently, fisetin was also found to induce autophagy; nevertheless, autophagy attenuation exaggerated apoptosis. Oral fisetin (50 mg/kg body weight) treatment to establish Cal33 xenograft in mice for 19 days showed 73% inhibition in tumor volume (p 
ISSN:0899-1987
1098-2744
1098-2744
DOI:10.1002/mc.23754