morin and Carcinoma--Squamous-Cell

Morin is a naturally occurring bioflavonoid originally isolated from members of the Moraceae family of flowering plants and it possesses antitumor activity in various human cancer cells. The present study explored the antitumor effects of morin in tongue squamous cell carcinoma (TSCC) cells in vitro and investigated the underlying molecular events. A TSCC cell line was treated with different doses of morin for up to 48 h. Analyses of cell viability, using Cell Counting Kit‑8 (CCK‑8), EdU incorporation, colony formation, flow cytometric analysis of cell cycle distribution and apoptosis, wound healing assay, western blot analysis and qRT‑PCR assays, were then performed. The data revealed that morin treatment reduced Cal27 cell proliferation and reduced the migration capacity of tumor cells in a dose‑dependent manner. Morin treatment also significantly upregulated mammalian sterile 20‑like 1 (MST1) and MOB kinase activator 1 (MOB1) phosphorylation in CAL27 cells, but suppressed nuclear translocation of yes‑associated protein (YAP) through the induction of YAP phosphorylation in Cal27 cells. Moreover, the expression of YAP‑targeting genes, such as CTGF, CYR61 and ANKRD, was downregulated in morin‑treated TSCC cells, indicating that morin was able to activate the Hippo signaling pathway to inhibit YAP nuclear translocation and YAP‑related transcriptional activity in TSCC cells. In conclusion, the data from the present study demonstrated that morin produces anti‑TSCC activity in vitro through activation of the Hippo signaling pathway and the downstream suppression of YAP activity in TSCC cells. Future studies should assess the clinical antitumor effects of morin.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Carcinoma, Squamous Cell; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Proliferation; Cell Survival; Down-Regulation; Drug Screening Assays, Antitumor; Flavonoids; Head and Neck Neoplasms; Hippo Signaling Pathway; Humans; Moraceae; Nuclear Proteins; Plant Extracts; Protein Serine-Threonine Kinases; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; Tongue Neoplasms; Transcription Factors; Up-Regulation

The major goal of cancer drug discovery is to find an agent that is safe and affordable, yet effective against cancer. Here we show that morin (3,5,7,2',4'-pentahydroxyflavone) has potential against cancer cells through suppression of the signal transducer and activator of transcription 3 (STAT3) pathway, which is closely linked to the transformation, survival, proliferation, and metastasis of cancer. We found that morin completely suppressed inducible and constitutively activated STAT3 and blocked the nuclear translocation of STAT3 and its DNA binding in multiple myeloma and head and neck squamous carcinoma cells. Morin inhibited activated Src, JAK-1, and JAK-2, all of which are linked to STAT3 activation, while up-regulating a protein inhibitor of activated STAT3, PIAS3. Pervanadate reversed the effects of morin on STAT3 phosphorylation, indicating the role of a protein tyrosine phosphatase. Furthermore, morin induced SHP1 expression at both the mRNA and protein levels, and silencing of SHP1 abrogated the effect of morin on STAT3 phosphorylation, indicating that morin mediates its effects on STAT3 through SHP1. Suppression of STAT3 correlated with the down-regulation of various gene products linked to tumor survival, proliferation, and angiogenesis and led to sensitization of tumor cells to thalidomide and bortezomib. Comparing the activities of morin with those of four structurally related flavonols demonstrated the importance of hydroxyl groups in the B ring in inhibiting STAT3 activation. These findings suggest that morin suppresses the STAT3 pathway, leading to the down-regulation of STAT3-dependent gene expression and chemosensitization of tumor cells.

Topics: Anticarcinogenic Agents; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Down-Regulation; Drug Screening Assays, Antitumor; Enzyme Activation; Flavonoids; Head and Neck Neoplasms; Humans; Multiple Myeloma; Neovascularization, Pathologic; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; RNA, Small Interfering; STAT3 Transcription Factor; Structure-Activity Relationship; Tyrosine

Topics: Antioxidants; Carcinoma, Squamous Cell; Cell Count; Cell Division; Cell Survival; Electron Transport Complex IV; Flavonoids; HeLa Cells; Humans; Indicators and Reagents; Laryngeal Neoplasms; Male; Middle Aged; Tumor Cells, Cultured