20(S)-ginsenoside Rh2 induces caspase-dependent promyelocytic leukemia-retinoic acid receptor A degradation in NB4 cells via Akt/Bax/caspase9 and TNF-α/caspase8 signaling cascades

Abstract

Background Acute promyelocytic leukemia (APL) is a hematopoietic malignancy driven by promyelocytic leukemia–retinoic acid receptor A (PML-RARA) fusion gene. The therapeutic drugs currently used to treat APL have adverse effects. 20( S )-ginsenoside Rh2 (GRh2) is an anticancer medicine with high effectiveness and low toxicity. However, the underlying anticancer mechanisms of GRh2-induced PML-RARA degradation and apoptosis in human APL cell line (NB4 cells) remain unclear. Methods Apoptosis-related indicators and PML-RARA expression were determined to investigate the effect of GRh2 on NB4 cells. Z-VAD-FMK, LY294002, and C 87, as inhibitors of caspase, and the phosphatidylinositol 3-kinase (PI3K) and tumor necrosis factor-α (TNF-α ) pathways were used to clarify the relationship between GRh2-induced apoptosis and PML-RARA degradation. Results GRh2 dose- and time-dependently decreased NB4 cell viability. GRh2-induced apoptosis, cell cycle arrest, and caspase3, caspase8, and caspase9 activation in NB4 cells after a 12-hour treatment. GRh2-induced apoptosis in NB4 cells was accompanied by massive production of reactive oxygen species, mitochondrial damage and upregulated Bax/Bcl-2 expression. GRh2 also induced PML/PML-RARA degradation, PML nuclear bodies formation, and activation of the downstream p53 pathway in NB4 cells. Z-VAD-FMK inhibited caspase activation and significantly reversed GRh2-induced apoptosis and PML-RARA degradation. GRh2 also upregulated TNF-α expression and inhibited Akt phosphorylation. LY294002, an inhibitor of the PI3K pathway, enhanced the antitumor effects of GRh2, and C 87, an inhibitor of the TNF-α pathway, reversed NB4 cell viability, and GRh2-mediated apoptosis in a caspase-8-dependent manner. Conclusion GRh2 induced caspase-dependent PML-RARA degradation and apoptosis in NB4 cells via the Akt/Bax/caspase9 and TNF-α/caspase8 pathways.

Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression

“… 90 , 91 AKT can be also phosphorylated and activated by PDK2 at Ser473. 92 , 93 Activated AKT regulates cell proliferation, differentiation, migration, and apoptosis by activating or inhibiting downstream target proteins, such as Bad, 94 Caspase9, 95 NF-κB, 96 , 97 GSK-3, 98 FKHR, 99 , 100 p21, 101 p53 102 and FOXO1. 103 , 104 Aberrant activation of PI3K/AKT pathway has been found in a variety of cancers, 105 such as lung cancer, 106 esophageal cancer, 107 gastric cancer, 108 breast cancer, 109 laryngeal cancer, 110 gallbladder cancer, 111 and prostate cancer.…”

The effects of Ginsenosides on PI3K/AKT signaling pathway

“… [ 6 ] Diabetic Nephropathy (DN) In vivo (Rat) - Rg1 0–50 µM Nephrin, α-SMA, GSK-3β, β-catenin AKT Ginsenoside Rg1 via the AKT/GSK-3β/β-catenin pathway could improve the tissue function of DN in rats. [ 7 ] Diabetes In vivo (Mouse), In vitro 3T3-L1 Rb2 40 mg/kg, 1–25 µM IKKβ, IκBɑ, IL-6, SOCS-3 PI3K/AKT Ginsenoside Rb2 via the PI3K/AKT pathway could decrease the accumulation of fat and regulate the resistance of insulin. [ 8 ] Diabetes Mellitus (T2DM) In vivo (Mouse), In vitro HepG2 Rg1 50 mg/kg, 10 µM PEPCK, G6Pase, FoxO1 AKT Ginsenoside Rg1 via AKT/FoxO1 axis could decrease gluconeogenesis to the response of fasting hormone glucagon in T2DM.…”

“…Ginsenoside Rg1 could prevent starvation-induced muscle protein degradation via regulating the AKT/mTOR/FoxO axis in C2C12 myotubes [ 31 ]. In addition, 20 (S)-ginsenoside Rg3 via regulating the AKT/mTOR/FoxO3 axis could protect against myotube atrophy [ 7 ]. Ginsenoside Rh2 could decrease inflammatory responses in the lung tissue and lung injury via PI3K/AKT/mTOR and MEK/ERK pathways [ 28 ].…”

Bacillus subtilis Produces Amino Acids to Stimulate Protein Synthesis in Ruminal Tissue Explants via the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta–Serine/Threonine Kinase–Mammalian Target of Rapamycin Complex 1 Pathway

“…Image J2x 2.1.4.7 Analyzer (Rawak Software Inc., Stuttgart, Germany) was used to quantify the intensity of each band. Refer to (27)(28)(29); LY294002 (50 µmol/L) and rapamycin (10 nmol/L; 9904) levels were determined with reference to previous studies and combined with the results of previous toxicity tests (30).…”