ER stress and ASK1-JNK activation contribute to oridonin-induced apoptosis and growth inhibition in cultured human hepatoblastoma HuH-6 cells

Abstract

Oridonin, the main active component of Rabdosia rubescens, has antitumor activities in experimental and clinical settings. The aims of the current study were to explore the anticancer abilities of oridonin in hepatoblastoma (HB) HuH-6 cells and to investigate the underlying mechanisms. We found that oridonin inhibited HuH-6 cell in vitro growth in a dose- and time-dependent manner. Further, oridonin induced HuH-6 cell apoptosis and G2/M cell cycle arrest. Upon studying the mechanism, we found that oridonin treatment caused endoplasmic reticulum (ER) stress activation. Meanwhile, ER stress inhibitor salubrinal- or inositol-requiring enzyme 1 (IRE-1) shRNA silencing inhibited oridonin's anti-HuH-6 effects, while ER stress inducers thapsigargin (Tg) and tunicamycin (Tm) mimicked oridonin's actions on HuH-6 cells. Oridonin also activated apoptosis signal regulating kinase 1 (ASK1)-c-Jun N-terminal kinase 1 (JNK1) signaling in cultured HuH-6 cells, which was inhibited by IRE-1 silencing. Importantly, the JNK inhibitors suppressed oridonin-induced growth inhibition and apoptosis in HuH-6 cells. In conclusion, our results suggest that oridonin induces growth inhibition and apoptosis in cultured HuH-6 cells involving ER stress and ASK1/JNK signaling pathways, which enhances our understanding of the molecular mechanisms of oridonin in HB management.

Caffeic acid improves cell viability and protects against DNA damage: involvement of reactive oxygen species and extracellular signal-regulated kinase

“…ROS can trigger the activation of redox-sensitive signal transduction and MAPK pathways that regulate cellular mechanisms of cell survival, death, and immunity (9,30,31). MAPKs including ERK, p38 MAPK, and JNK are key components of signaling pathways that control cell differentiation and growth (9,30,31).…”

“…MAPKs including ERK, p38 MAPK, and JNK are key components of signaling pathways that control cell differentiation and growth (9,30,31). There is evidence that MAPKs can be phosphorylated and activated in response to oxidant-induced alterations of the redox state (7).…”

“…There is evidence that MAPKs can be phosphorylated and activated in response to oxidant-induced alterations of the redox state (7). After activation, each MAPK phosphorylates a distinct spectrum of substrates including key regulatory enzymes, cytoskeletal proteins, regulators of apoptosis, nuclear receptors, and many transcription factors that bind to specific DNA sequences and induce transcriptional activation and DNA synthesis, with cellular recruitment to the S-phase (9,30,32). CaA regulates LPS-induced oxidative stress through c-Src/ERK signaling pathways in endothelial cells (4).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…As an orally available drug, oridonin is demonstrated to have anti-cancer activities in multiple cancers over the past decades, including leukemia, lymphoma, osteosarcoma, myeloma, uveal melanoma, neuroblastoma, hepatocellular, laryngeal, esophageal, and oral squamous cell carcinoma, lung, colorectal, breast, gastric, pancreatic, and prostatic cancers [543][544][545][546][547][548][549][550][551][552][553][554][555][556][557][558]. The anti-cancer effects of oridonin are shown in many aspects, including the induction of cell apoptosis, autophagy, cell cycle arrest, and the suppression of angiogenesis, cell migration, invasion and adhesion [554,[559][560][561][562][563][564].…”

Oridonin induces apoptosis through the mitochondrial pathway in human gastric cancer SGC-7901 cells

“…1), is a diterpenoid compound (10). Previous studies have shown that oridonin has antitumor activities in vivo and in vitro (11)(12)(13), and oridonin inhibited proliferation of cancer cells by inducing autophagic pathways (14)(15)(16)(17)(18), arresting the cell cycle on G 0 /G 1 phase (19) or G 2 /M phase (20)(21)(22)(23)(24), inducing apoptosis of human laryngeal cancer cells (25), esophageal cancer (26), colorectal carcinoma (27), pancreatic cancer (28), hepato cellular carcinoma (29,30). However, few reports exist on oridonin-induced apoptosis on gastric cancer.…”