Myricetin induces apoptosis by inhibiting P21 activated kinase 1 (PAK1) signaling cascade in hepatocellular carcinoma

• Published in: Molecular and cellular biochemistry Vol. 407; no. 1-2; pp. 223 - 237
• Main Authors: Iyer, Soumya C., Gopal, Ashidha, Halagowder, Devaraj
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2015; Springer; Springer Nature B.V
• Subjects: Analgesics - administration & dosage; Analgesics - pharmacology; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cancer; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Cardiology; Cell Proliferation - drug effects; Flavonoids - administration & dosage; Flavonoids - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Health aspects; Hep G2 Cells; Hepatocellular carcinoma; Hepatology; Humans; Kinases; Life Sciences; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - pathology; Male; Medical Biochemistry; Oncology; p21-Activated Kinases - genetics; p21-Activated Kinases - metabolism; Rats; Signal transduction; Signal Transduction - drug effects; Xenograft Model Antitumor Assays; Erk1/2; β-Catenin; PAK1; Myricetin
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-015-2471-6

Hepatocellular carcinoma is one of the most common malignancies worldwide and evidence suggests that Ras signaling regulates various hallmarks of cancer via regulating several effector pathways such as ERK and PI3K. The aim of the present study is to understand the efficacy of a flavonoid myricetin for the first time in inhibiting the downstream target p21 activated kinase 1 (PAK1) of Ras signaling pathway in hepatocellular carcinoma. The analysis of gene expression revealed that myricetin inhibits PAK1 by abrogating the Ras-mediated signaling by decelerating Wnt signaling, the downstream of Erk/Akt, thereby inducing intrinsic caspase-mediated mitochondrial apoptosis by downregulating the expression of anti-apoptotic Bcl-2 and survivin and upregulating pro-apoptotic Bax. The results also provide striking evidence that the myricetin inhibits the development of HCC by inhibiting PAK1 via coordinate abrogation of MAPK/ERK and PI3K/AKT and their downstream signaling Wnt/β-catenin pathway, thus being a promising candidate for cancer prevention and therapy.