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Protein phosphatase 2A (PP2A), a heterotrimeric holoenzyme (scaffolding, catalytic, and regulatory subunits), regulates dephosphorylation for more than half of serine/threonine phosphosites and exhibits diverse cellular functions. Although several studies on natural products and miRNAs have emphasized their impacts on PP2A regulation, their connections lack systemic organization. Moreover, only part of the PP2A family has been investigated. This review focuses on the PP2A-modulating effects of natural products and miRNAs' interactions with potential PP2A targets in cancer and non-cancer cells. PP2A-modulating natural products and miRNAs were retrieved through a literature search. Utilizing the miRDB database, potential PP2A targets of these PP2A-modulating miRNAs for the whole set (17 members) of the PP2A family were retrieved. Finally, PP2A-modulating natural products and miRNAs were linked via a literature search. This review provides systemic directions for assessing natural products and miRNAs relating to the PP2A-modulating functions in cancer and disease treatments., (© 2024 Wiley Periodicals LLC.)

Antioral cancer drugs need a greater antiproliferative impact on cancer than on normal cells. Demethoxymurrapanine (DEMU) inhibits proliferation in several cancer cells, but an in-depth investigation was necessary. This study evaluated the proliferation-modulating effects of DEMU, focusing on oral cancer and normal cells. DEMU (0, 2, 3, and 4 μg/mL) at 48 h treatments inhibited the proliferation of oral cancer cells (the cell viability (%) for Ca9-22 cells was 100.0 ± 2.2, 75.4 ± 5.6, 26.0 ± 3.8, and 15.4 ± 1.4, and for CAL 27 cells was 100.0 ± 9.4, 77.2 ± 5.9, 57.4 ± 10.7, and 27.1 ± 1.1) more strongly than that of normal cells (the cell viability (%) for S-G cells was 100.0 ± 6.6, 91.0 ± 4.6, 95.0 ± 2.6, and 95.8 ± 5.5), although this was blocked by the antioxidant N-acetylcysteine. The presence of oxidative stress was evidenced by the increase of reactive oxygen species and mitochondrial superoxide and the downregulation of the cellular antioxidant glutathione in oral cancer cells, but these changes were minor in normal cells. DEMU also caused greater induction of the subG1 phase, extrinsic and intrinsic apoptosis (annexin V and caspases 3, 8, and 9), and DNA damage (γH2AX and 8-hydroxy-2-deoxyguanosine) in oral cancer than in normal cells. N-acetylcysteine attenuated all these DEMU-induced changes. Together, these data demonstrate the preferential antiproliferative function of DEMU in oral cancer cells, with the preferential induction of oxidative stress, apoptosis, and DNA damage in these cancer cells, and low cytotoxicity toward normal cells., (© 2023 Wiley Periodicals LLC.)

The antibiotic antimycin A (AMA) is commonly used as an inhibitor for the electron transport chain but its application in anticancer studies is rare. Recently, the repurposing use of AMA in antiproliferation of several cancer cell types has been reported. However, it is rarely investigated in oral cancer cells. The purpose of this study is to investigate the selective antiproliferation ability of AMA treatment on oral cancer cells. Cell viability, flow cytometry, and western blotting were applied to explore its possible anticancer mechanism in terms of both concentration- and exposure time-effects. AMA shows the higher antiproliferation to two oral cancer CAL 27 and Ca9-22 cell lines than normal oral HGF-1 cell lines. Moreover, AMA induces the production of higher reactive oxygen species (ROS) levels and pan-caspase activation in oral cancer CAL 27 and Ca9-22 cells than in normal oral HGF-1 cells, providing the possible mechanism for its selective antiproliferation effect of AMA. In addition to ROS, AMA induces mitochondrial superoxide (MitoSOX) generation and depletes mitochondrial membrane potential (MitoMP). This further supports the AMA-induced oxidative stress changes in oral cancer CAL 27 and Ca9-22 cells. AMA also shows high expressions of annexin V in CAL 27 and Ca9-22 cells and cleaved forms of poly (ADP-ribose) polymerase (PARP), caspase 9, and caspase 3 in CAL 27 cells, supporting the apoptosis-inducing ability of AMA. Furthermore, AMA induces DNA damage (γH2AX and 8-oxo-2'-deoxyguanosine [8-oxodG]) in CAL 27 and Ca9-22 cells. Notably, the AMA-induced selective antiproliferation, oxidative stress, and DNA damage were partly prevented from N-acetylcysteine (NAC) pretreatments. Taken together, AMA selectively kills oral cancer cells in an oxidative stress-dependent mechanism involving apoptosis and DNA damage., (© 2020 Wiley Periodicals LLC.)

Discovering drug candidates for the modulation of metastasis is of great importance in inhibiting oral cancer malignancy. Although most pomegranate extract applications aim at the antiproliferation of cancer cells, its antimetastatic effects remain unclear, especially for oral cancer cells. The aim of this study is to evaluate the change of two main metastasis characters, migration and invasion of oral cancer cells. Further, we want to explore the molecular mechanisms of action of pomegranate extract (POMx) at low cytotoxic concentration. We found that POMx ranged from 0 to 50 μg/mL showing low cytotoxicity to oral cancer cells. In the case of oral cancer HSC-3 and Ca9-22 cells, POMx inhibits wound healing migration, transwell migration, and matrix gel invasion. Mechanistically, POMx downregulates matrix metalloproteinase (MMP)-2 and MMP-9 activities and expressions as well as epithelial-mesenchymal transition (EMT) signaling. POMx upregulates extracellular signal-regulated kinases 1/2 (ERK1/2), but not c-Jun N-terminal kinase (JNK) and p38 expression. Addition of ERK1/2 inhibitor (PD98059) significantly recovered the POMx-suppressed transwell migration and MMP-2/-9 activities in HSC-3 cells. Taken together, these findings suggest to further test low cytotoxic concentrations of POMx as a potential antimetastatic therapy against oral cancer cells., (© 2020 Wiley Periodicals, Inc.)

Geraniin has been reported to have numerous biological activities, including antiviral, antihypertensive, antihyperglycaemic, liver protective, antidiabetic, and apoptotic activities. However, the anti-migration effects of geraniin on oral cancer remain elusive. In this study, we revealed the potential antitumor mechanisms of geraniin through the inhibition of the migration and invasion of human oral cancer cell lines SCC-9 and SCC-14. The results of gelatin zymography and Western blot assays revealed that geraniin significantly reduced the activity and expression of matrix metalloproteinase-2 (MMP-2) of oral cancer cells in a concentration-dependent manner. Furthermore, geraniin potently suppressed the phosphorylation of focal adhesion kinase (FAK), Src, and extracellular signal-regulated kinase (ERK)1/2 but did not affect the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase 1/2. Moreover, blocking the MAPK/ERK1/2 pathway significantly enhanced the anti-migration ability of geraniin in oral cancer cells. In conclusion, we demonstrated that geraniin inhibits the motility of SCC-9 and SCC-14 cells in vitro through a molecular mechanism that involves the attenuation of MMP-2 expression and activity mediated by decreased FAK/Src and ERK1/2 pathways., (© 2019 Wiley Periodicals, Inc.)

Tricetin is a flavonoid derivative and a potent anti-inflammatory and anticancer agent. However, the molecular mechanism underlying the effects of tricetin on human oral cancer cell migration remains unclear. The cell migration and invasion abilities of three oral cancer cell lines (SCC-9, HSC-3, and OECM-1) were analyzed using Boyden chamber migration assays. Our results demonstrated that tricetin attenuates 12-O-tetradecanoylphorbol-13-acetate-induced SCC-9, HSC-3, and OECM-1 cell invasiveness and migration by reducing matrix metalloproteinase (MMP)-9 enzyme activity. The reverse transcription polymerase chain reaction and luciferase reporter assay revealed that tricetin downregulates the mRNA expression and promoter activity of MMP-9. In addition, Western blot analysis revealed that tricetin significantly reduced the levels of phosphorylated c-Jun N-terminal kinase (JNK) 1/2 and p38 levels but not those of extracellular signal-regulated kinase 1/2. In conclusion, this study demonstrated that tricetin suppresses MMP-9 enzymatic activity by downregulating the p38/JNK1/2 pathway and might be a beneficial chemopreventive agent., (© 2017 Wiley Periodicals, Inc.)