Fisetin induces apoptosis in human skin cancer cells through downregulating MTH1
Khalid Imtiyaz1, Arshad Husain Rahmani2, Mohammed A Alsahli2
1Department of Bioscience, Genome Biology Lab, New Delhi, India.
Abstract:
Fisetin, a natural flavonoid molecule, has been shown to have anticancer properties against various malignancies. In this investigation, we discovered that Fisetin decreased cell viability of both the treated skin cancer cell lines A375 and A431 in a dose and time-dependent manner. The IC50 values ranging from 57.60 µM ± 6.59 to 41.70 µM ± 1.25 in A375 and 48.70 µM ± 5.49 to 33.67 µM ± 1.03 for A431 at the observed time ranging between 24 h to 72 h of treatment remained quite enthusiastic when compared with the normal HEK 293 cells. Fisetin significantly decreased colony formation and migratory ability of the cancer cells. Flow cytometry analysis revealed that Fisetin significantly restricted the progression of skin cancer cells in the G0/G1 phase of the cell cycle and induced cells to undergo apoptosis by increasing reactive oxygen species, decreasing mitochondrial membrane potential, and elevating the count of early and late apoptotic cells. Our in silico studies of molecular docking followed by molecular dynamics simulation found that the interactions and stability of MTH1 protein with Fisetin further showed a considerable binding affinity for MTH1 (-11.4 kcal/mol) and developed stable complexes maintained throughout 100 ns trajectories. Our western blot analysis endorsed this. We found that Fisetin downregulated the expression levels of MTH1 also in addition, it played a crucial role in regulation of apoptotic events in cancer cells. We therefore, conclude that Fisetin anticancer properties against skin cancer cells are mediated through MTH1 inhibition followed by ATM and P53 upregulation.Communicated by Ramaswamy H. Sarma.
Insights
Fisetin, a natural compound, effectively combats skin cancer by inhibiting MTH1 protein. This leads to reduced cancer cell viability, migration, and increased apoptosis, offering a promising therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Fisetin is a natural flavonoid with demonstrated anticancer potential.
- Skin cancers, including melanoma, represent a significant global health challenge.
- Targeting specific molecular pathways is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the anticancer effects of Fisetin on human skin cancer cell lines (A375 and A431).
- To elucidate the molecular mechanisms underlying Fisetin's anti-skin cancer activity, focusing on MTH1 protein.
- To evaluate the potential of Fisetin as a therapeutic agent for skin malignancies.
Main Methods:
- Cell viability assays (IC50 determination) and colony formation assays.
- Cell migration assays and flow cytometry for cell cycle analysis and apoptosis induction.
- In silico molecular docking and molecular dynamics simulations of Fisetin with MTH1 protein.
- Western blot analysis to assess MTH1, ATM, and P53 protein expression.
Main Results:
- Fisetin significantly reduced viability and colony formation in A375 and A431 skin cancer cells in a dose- and time-dependent manner.
- Fisetin inhibited cancer cell migration and induced apoptosis by altering reactive oxygen species levels, mitochondrial membrane potential, and cell cycle progression (G0/G1 arrest).
- In silico and western blot analyses confirmed Fisetin's strong binding affinity to MTH1, leading to its downregulation and subsequent upregulation of ATM and P53.
Conclusions:
- Fisetin exhibits potent anticancer properties against skin cancer cells.
- The anticancer effects of Fisetin are mediated through the inhibition of MTH1 protein, leading to apoptosis.
- Fisetin's mechanism involves MTH1 downregulation, followed by ATM and P53 upregulation, highlighting its therapeutic potential.
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