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Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis by regulating p38 MAPKs and PI3K/AKT signaling pathways.

Pan BS, Wang YK, Lai MS, Mu YF, Huang BM - Sci Rep (2015)

Bottom Line: Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP.Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells.These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.

View Article: PubMed Central - PubMed

Affiliation: Institute of Basic Medical Sciences, College of Medicine, National Chen Kung University, Tainan, Taiwan, Republic of China.

ABSTRACT
The p38 MAPKs play important roles in the regulation of balance between cell survival and cell death on the development of various cancers. However, the roles of p38 MAPKs regulating apoptotic effects on Leydig tumor cells remain unclear. In the present study, we showed that cordycepin (3'-deoxyadenosine) selectively induced apoptosis in MA-10 mouse Leydig tumor cells through regulating the p38 MAPK and PI3K/AKT signaling pathways. Cordycepin reduced viability in MA-10, TM4, and NT2/D1 cells, but not cause cell death of primary mouse Leydig cells on moderate concentration. Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP. Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells. Co-treatment with wortmannin or the autophagy inhibitor 3-methyladenine (3-MA) elevated levels of apoptosis in cordycepin-treated MA-10 cells. Moreover, cordycepin activated p53, p21 and TGFß; and downregulated CDK2. The antitumour activity of cordycepin-treated MA-10 cells was significantly distinct in severe combined immunodeficiency (SCID) mice in vivo. These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of cordycepin triggers apoptosis of MA-10 mouse Leydig tumor cells through p38, caspase, and PI3K/AKT/mTOR signaling pathways.Cordycepin treatment is able to induce the activation of p38. The activation of p38 is able to induce a cascade of events that include cleaved caspase-3 and PARP activation resulting in the induction of apoptosis. Cleaved caspase-3 also can be triggered by either death receptor-dependent or mitochondrion-dependent signaling pathways to promote the terminal phase of apoptosis. It should be also noted that treatment of cordycepin promotes MA-10 cell apoptosis through the activation of p53-dependent pathways and accumulation of ROS level. These signaling pathways associate and induce cell cycle arrest, leading to the final stages of apoptosis. Cordycepin also induced autophagy by suppressing PI3K/AKT/mTOR pathways. The molecular mechanism triggered by cordycepin in the MA-10 mouse Leydig tumor cells and this mechanism may be a model for future targets of cancer treatment. Potential major pathways are indicated by large arrowhead, and potential minor pathways are indicated by slight arrowhead.
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f8: Schematic representation of cordycepin triggers apoptosis of MA-10 mouse Leydig tumor cells through p38, caspase, and PI3K/AKT/mTOR signaling pathways.Cordycepin treatment is able to induce the activation of p38. The activation of p38 is able to induce a cascade of events that include cleaved caspase-3 and PARP activation resulting in the induction of apoptosis. Cleaved caspase-3 also can be triggered by either death receptor-dependent or mitochondrion-dependent signaling pathways to promote the terminal phase of apoptosis. It should be also noted that treatment of cordycepin promotes MA-10 cell apoptosis through the activation of p53-dependent pathways and accumulation of ROS level. These signaling pathways associate and induce cell cycle arrest, leading to the final stages of apoptosis. Cordycepin also induced autophagy by suppressing PI3K/AKT/mTOR pathways. The molecular mechanism triggered by cordycepin in the MA-10 mouse Leydig tumor cells and this mechanism may be a model for future targets of cancer treatment. Potential major pathways are indicated by large arrowhead, and potential minor pathways are indicated by slight arrowhead.

Mentions: Based on these results, we generated a model illustrating how cordycepin treatment is able to induce the apoptosis of MA-10 cells (Fig. 8). The activation of p38 is able to induce a cascade of events that include cleaved caspase-3 and PARP activation resulting in the induction of apoptosis. Cleaved caspase-3 also can be triggered by either death receptor-dependent or mitochondrion-dependent signaling pathways to promote the terminal phase of apoptosis. It should be also noted that treatment of cordycepin promotes MA-10 cell apoptosis through the activation of p53-dependent pathways and accumulation of ROS level. These signaling pathways associate and induce cell cycle arrest, leading to the final stages of apoptosis. Cordycepin also induced autophagy by suppressing PI3K/AKT/mTOR pathways. The molecular mechanism triggered by cordycepin in the MA-10 mouse Leydig tumor cells and this mechanism may be a model for future targets of cancer treatment.


Cordycepin induced MA-10 mouse Leydig tumor cell apoptosis by regulating p38 MAPKs and PI3K/AKT signaling pathways.

Pan BS, Wang YK, Lai MS, Mu YF, Huang BM - Sci Rep (2015)

Schematic representation of cordycepin triggers apoptosis of MA-10 mouse Leydig tumor cells through p38, caspase, and PI3K/AKT/mTOR signaling pathways.Cordycepin treatment is able to induce the activation of p38. The activation of p38 is able to induce a cascade of events that include cleaved caspase-3 and PARP activation resulting in the induction of apoptosis. Cleaved caspase-3 also can be triggered by either death receptor-dependent or mitochondrion-dependent signaling pathways to promote the terminal phase of apoptosis. It should be also noted that treatment of cordycepin promotes MA-10 cell apoptosis through the activation of p53-dependent pathways and accumulation of ROS level. These signaling pathways associate and induce cell cycle arrest, leading to the final stages of apoptosis. Cordycepin also induced autophagy by suppressing PI3K/AKT/mTOR pathways. The molecular mechanism triggered by cordycepin in the MA-10 mouse Leydig tumor cells and this mechanism may be a model for future targets of cancer treatment. Potential major pathways are indicated by large arrowhead, and potential minor pathways are indicated by slight arrowhead.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4548195&req=5

f8: Schematic representation of cordycepin triggers apoptosis of MA-10 mouse Leydig tumor cells through p38, caspase, and PI3K/AKT/mTOR signaling pathways.Cordycepin treatment is able to induce the activation of p38. The activation of p38 is able to induce a cascade of events that include cleaved caspase-3 and PARP activation resulting in the induction of apoptosis. Cleaved caspase-3 also can be triggered by either death receptor-dependent or mitochondrion-dependent signaling pathways to promote the terminal phase of apoptosis. It should be also noted that treatment of cordycepin promotes MA-10 cell apoptosis through the activation of p53-dependent pathways and accumulation of ROS level. These signaling pathways associate and induce cell cycle arrest, leading to the final stages of apoptosis. Cordycepin also induced autophagy by suppressing PI3K/AKT/mTOR pathways. The molecular mechanism triggered by cordycepin in the MA-10 mouse Leydig tumor cells and this mechanism may be a model for future targets of cancer treatment. Potential major pathways are indicated by large arrowhead, and potential minor pathways are indicated by slight arrowhead.
Mentions: Based on these results, we generated a model illustrating how cordycepin treatment is able to induce the apoptosis of MA-10 cells (Fig. 8). The activation of p38 is able to induce a cascade of events that include cleaved caspase-3 and PARP activation resulting in the induction of apoptosis. Cleaved caspase-3 also can be triggered by either death receptor-dependent or mitochondrion-dependent signaling pathways to promote the terminal phase of apoptosis. It should be also noted that treatment of cordycepin promotes MA-10 cell apoptosis through the activation of p53-dependent pathways and accumulation of ROS level. These signaling pathways associate and induce cell cycle arrest, leading to the final stages of apoptosis. Cordycepin also induced autophagy by suppressing PI3K/AKT/mTOR pathways. The molecular mechanism triggered by cordycepin in the MA-10 mouse Leydig tumor cells and this mechanism may be a model for future targets of cancer treatment.

Bottom Line: Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP.Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells.These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.

View Article: PubMed Central - PubMed

Affiliation: Institute of Basic Medical Sciences, College of Medicine, National Chen Kung University, Tainan, Taiwan, Republic of China.

ABSTRACT
The p38 MAPKs play important roles in the regulation of balance between cell survival and cell death on the development of various cancers. However, the roles of p38 MAPKs regulating apoptotic effects on Leydig tumor cells remain unclear. In the present study, we showed that cordycepin (3'-deoxyadenosine) selectively induced apoptosis in MA-10 mouse Leydig tumor cells through regulating the p38 MAPK and PI3K/AKT signaling pathways. Cordycepin reduced viability in MA-10, TM4, and NT2/D1 cells, but not cause cell death of primary mouse Leydig cells on moderate concentration. Cordycepin increased reactive oxygen species (ROS) levels, which is associated with the induction of apoptosis as characterized by positive Annexin V binding, activation of caspase-3, and cleavage of PARP. Inhibition of p38 MAPKs activity by SB203580 significantly prevented cordycepin-induced apoptosis in MA-10 cells. Co-treatment with wortmannin or the autophagy inhibitor 3-methyladenine (3-MA) elevated levels of apoptosis in cordycepin-treated MA-10 cells. Moreover, cordycepin activated p53, p21 and TGFß; and downregulated CDK2. The antitumour activity of cordycepin-treated MA-10 cells was significantly distinct in severe combined immunodeficiency (SCID) mice in vivo. These results suggested that cordycein is a highly selective treatment to induce MA-10 cells apoptosis via p38 MAPKs signaling.

No MeSH data available.


Related in: MedlinePlus