Abstract
Malignant melanoma is characterized by its bad prognosis for aggressiveness, drug resistance, and early metastasis. Isorhamnetin (3′-methoxy-3,4′,5,7-tetrahydroxyflavone; IH) is a natural flavonoid that has been investigated for its antitumor effects in breast cancer, colon cancer, and gastric cancer through inducing cell apoptosis. Given its role in tumor inhibition, no research has been conducted concerning its effect against melanoma. In the present study, we found that IH could significantly inhibit B16F10 cell proliferation and migration and induce B16F10 cell apoptosis. The examination on molecular mechanism revealed that IH could suppress the phosphorylation of Akt and the translocation of NF-κB, which are key factors in apoptosis-related pathways. We also detected that this process was related to the bifunctional 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases 4 (PFKFB4) by PFKFB4 knockdown experiment. In line with in vitro study, we further provided that IH effectively inhibited tumor growth in vivo. Taken together, IH was proven to induce melanoma cell apoptosis in vitro and in vivo, which may serve as a potential agent in malignant melanoma treatment in the future.
Highlights
Malignant melanoma is the most fatal form of skin cancer, which accounts for 80% death of all types of skin cancer and 3% death of all malignant tumors
Our results indicated that IH attenuated B16F10 melanoma cell proliferation and migration and promoted cell apoptosis in a dose-dependent manner
Several studies have focused on the effect of IH on the inhibition of cell proliferation as well as induction of apoptosis on various types of tumors, including nonmelanoma skin cancer (NMSC) [15] and bladder cancer [16]
Summary
Malignant melanoma is the most fatal form of skin cancer, which accounts for 80% death of all types of skin cancer and 3% death of all malignant tumors. [1] Currently, there are different types of treatments for patients depending on the stage of melanoma. These treatments are limited due to tumor aggressiveness, tumor recurrence, and drug resistance. The phosphatidylinositol-3-OH kinase (PI3K) pathway is a well-acknowledged key signal pathway in cell cycle, apoptosis, and proliferation, which makes it an important target in multiple tumor types. It was reported that the activity of the PI3K/Akt pathway is increased in 70% sporadic melanoma. [1] The kinase Akt functions as a central integrator of PI3K signalling to modulate downstream effectors, which are primary regulators of protein synthesis and cell growth. It was reported that the activity of the PI3K/Akt pathway is increased in 70% sporadic melanoma. [1] The kinase Akt functions as a central integrator of PI3K signalling to modulate downstream effectors, which are primary regulators of protein synthesis and cell growth. [1]
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