Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells

Hsu, Shu-Shong; Huang, Chun-Ta; Cheng, He‐Hsiung; Chou, Chiang-Ting; Lee, Hsiao-Ying; Wang, Jue‐Long; Chen, I-Shu; Liu, Shiuh–Inn; Lu, Yih-Chau; Chang, Hong‐Tai; Huang, Jong‐Khing; Chen, Jin-Shyr; Jan, Chung‐Ren

doi:10.1016/j.tox.2006.11.005

Cited by 44 publications

(34 citation statements)

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“…Previous reports showed that p38-MAPK is involved in apoptosis [14,23] and activated during the GC-induced apoptosis [15,19]. Recent studies demonstrated that p38-MAPK plays many critical roles in apoptosis and survival in osteoblasts [16,17].…”

Section: Discussionmentioning

confidence: 98%

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Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

et al. 2008

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Glucocorticoids (GCs), which play an important role in the normal regulation of bone remodeling, are widely used as anti-inflammatory and chemotherapeutic agents. However, continued exposure to GCs results in osteoporosis, which is partially due to apoptosis of osteoblasts and osteocytes. To understand the mechanism of how GCs induce cell death in osteoblasts, we examined apoptotic effects of dexamethasone (Dex), GC, on MC3T3-E1 osteoblast cells. Results revealed that Dex-induced apoptosis was inhibited by a GC receptor antagonist, mifepristone, and a general caspase inhibitor, Z-VAD-fmk, indicating that Dex induces apoptosis of MC3T3-E1 cells through the pathways involved in GC receptor and caspase. Glycogen synthase kinase 3b (GSK3b) is known to participate in apoptosis signaling in MC3T3-E1 cells. Dex activated both GSK3b and p38-mitogen-activated protein kinase (MAPK). The inhibition of GSK3b by inhibitor (LiCl) or small interference RNA (siRNA) decreased apoptosis. In contrast, the inhibition of p38-MAPK by inhibitor (SB203580) or siRNA did not decrease, but increase apoptosis. These results suggest that Dex-mediated apoptosis of osteoblasts is facilitated by GSK3b, but prevented by p38-MAPK.

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Section: Discussionmentioning

confidence: 98%

“…The p38-MAPK activation is essential for differentiation of osteoblasts [13]. However, p38-MAPK phosphorylation in osteosarcoma and osteoblasts cells is related to apoptosis through the subsequent activation of caspase-3 [14,15]. The p38-MAPK has been shown to play many important roles in apoptosis and survival in osteoblasts [16,17].…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

et al. 2008

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“…The MAPK signaling pathway has been exploited in cancer treatment because of its key roles in inflammation, cell-cycle regulation, cell death, development, differentiation, senescence, and tumorigenesis (15,16). A recent study also demonstrated that anandamide activated caspase-3 through an increase in p38 MAPK phosphorylation in osteosarcoma cells (18). However, further studies are needed to clearly understand how dihydromyricetin induces AMPK activation, which can be caused by generating more reactive oxygen species (ROS) or other metabolic stress.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that the activation of the MAPK signaling pathway, which includes p38 MAPK , JNK pan, and the downstream target MSK1/2, could induce cancer cell death (15, 32). In osteosarcoma cells, the P38 MAPK phosphorylation subsequently activated caspase-3, leading to apoptosis or regulated Eag channel functions (33,34). Therefore, we further investigated the expression of the AMPKa and p38 MAPK signaling pathways in U2OS and ZOS cells treated with the indicated doses of dihydromyricetin.…”

Section: Activation Of Ampka and P38 Mapk May Play A Role In The Antimentioning

confidence: 99%

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Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

Zhao

Yin

et al. 2014

Cancer Prevention Research

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Numerous patients with osteosarcoma either are not sensitive to chemotherapy or develop drug resistance to current chemotherapy regimens. Therefore, it is necessary to develop several potentially useful therapeutic agents. Dihydromyricetin is the major flavonoid component derived from Ampelopsis grossedentata, which has a long history of use in food and medicine. The present study examined the antitumor activity both in vitro and in vivo without noticeable side effects and the underlying mechanism of action of dihydromyricetin in osteosarcoma cells. We found that dihydromyricetin induced increased p21 expression and G 2 -M cellcycle arrest, caused DNA damage, activated ATM-CHK2-H2AX signaling pathways, and induced apoptosis in osteosarcoma cells as well as decreasing the sphere formation capability by downregulating Sox2 expression. Mechanistic analysis showed that the antitumor potential of dihydromyricetin may be due to the activation of AMPKa and p38 MAPK , as the activating AMPKa led to the inactivation of GSK3b in osteosarcoma cells. Moreover, GSK3b deletion or GSK3b inhibition by LiCl treatment resulted in increased p21 expression and reduced Sox2 expression in osteosarcoma cells. Taken together, our results strongly indicate that the antitumor potential of dihydromyricetin is correlated with P38 MAPK and the AMPKaGSK3b-Sox2 signaling pathway. Finally, immunohistochemical analysis indicated that some patients had a lower p-AMPK expression after chemotherapy, which supports that the combination of dihydromyricetin and chemotherapy drug will be beneficial for patients with osteosarcoma. In conclusion, our results are the first to suggest that dihydromyricetin may be a therapeutic candidate for the treatment of osteosarcoma. Cancer Prev Res; 7(9); 927-38. Ó2014 AACR.

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Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

et al. 2014

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Endocannabinoids has been described to be involved in articular degenerative disease by modulating nociception and immune system. However, the role of the endocannabinoid anandamide on chondrocyte cell viability is still unclear. Therefore, we decided to study anandamide's effects on chondrocytes viability and to evaluate its interactions with the catabolic factor TNF (tumor necrosis factor). Chondrocyte vitality was evaluated by MTT assay. We investigated LDH release, chromatin condensation, cleavage of focal adhesion kinase (FAK), and caspases-3, 8, and 9 activation. c-MYC mRNA levels were determined by RT-PCR. We studied by Western blot the activation patterns of AKT, AMPK, ERK, p38, and JNK kinases. Finally, we evaluate the effect of anandamide in TNF-induced caspase-3 cleavage. Anandamide decreased chondrocyte vitality independently of its receptors. It induced AMPK activation without LDH release. Anandamide induced chromatin condensation, activation of caspase-3, 8, and 9, and FAK cleavage. Surprisingly, despite anandamide inhibited cell proliferation, it increased c-MYC expression. Moreover anandamide inhibited AKT activation, whilst it induced a sustained activation of ERK, JNK, and p38. Finally, anandamide synergized with TNF-a in the cleavage of caspase-3. In conclusion, our findings suggest that anandamide, alone or in combination with TNF-a, may be a potential destructive agent in cartilage. Keywords: cannabinoids; chondrocyte physiology; apoptosis; signal transduction; TNF The endocannabinoid system is constituted by the cannabinoid receptors (CB 1 and CB 2 ), by the endocannabinoids (including anandamide [AEA] and others) and the machinery for their biosynthesis and metabolism.

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Anandamide-induced Ca2+ elevation leading to p38 MAPK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells

Cited by 44 publications

References 45 publications

Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3β

Dihydromyricetin Activates AMP-Activated Protein Kinase and P38MAPK Exerting Antitumor Potential in Osteosarcoma

Endogenous cannabinoid anandamide impairs cell growth and induces apoptosis in chondrocytes

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