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Ephrin type‑A receptor 2 regulates sensitivity to paclitaxel in nasopharyngeal carcinoma via the phosphoinositide 3‑kinase/Akt signalling pathway.

Wang Y, Liu Y, Li G, Su Z, Ren S, Tan P, Zhang X, Qiu Y, Tian Y - Mol Med Rep (2014)

Bottom Line: In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5‑8F cells, compared with control cells exposed to the same concentrations of paclitaxel.Furthermore, paclitaxel stimulation and EphA2 over‑expression resulted in activation of the phosphoinositide 3‑kinase (PI3K)/Akt signalling pathway in NPC cells.The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.

ABSTRACT
Ephrin type‑A receptor 2 (EphA2) is a receptor tyrosine kinase that is associated with cancer cell metastasis. There has been little investigation into its impact on the regulation of sensitivity to paclitaxel in nasopharyngeal carcinoma (NPC). In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5‑8F cells, compared with control cells exposed to the same concentrations of paclitaxel. Flow cytometry and western blot analysis demonstrated that over‑expression of EphA2 decreased NPC cancer cell sensitivity to paclitaxel by regulating paclitaxel‑mediated cell cycle progression but not apoptosis in vitro. This was accompanied by alterations in the expression of cyclin‑dependent kinase inhibitors, p21 and p27, and of inactive phosphorylated‑retinoblastoma protein. Furthermore, paclitaxel stimulation and EphA2 over‑expression resulted in activation of the phosphoinositide 3‑kinase (PI3K)/Akt signalling pathway in NPC cells. Inhibition of the PI3K/Akt signalling pathway restored sensitivity to paclitaxel in 5‑8F cells over‑expressing EphA2, which indicated that the PI3K/Akt pathway is involved in EphA2‑mediated paclitaxel sensitivity. The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC.

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EphA2 mediated paclitaxel sensitivity in NPC 5–8 cells via modulation of the PI3K/Akt signalling pathway. (A) PI3K/Akt signalling pathway inhibitor, LY294002, reverses paclitaxel resistance caused by EphA2 over-expression. (B) Effect of LY294002 on the cell-cycle distribution in EphA2 over-expressing NPC cells pre-treated with paclitaxel. (C) Effect of LY294002 on the apoptotic rate in NPC cells over-expressing EphA2, pretreated with paclitaxel. (D) LY294002 restores the changes in expression of cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1, caused by EphA2 over-expression. *P<0.05. EphA2, ephrin type-A receptor 2; NPC, nasopharyngeal carcinoma; PI3K, phosphoinositide 3-kinase; p-Akt, phsophorylated Akt; Rb, retinoblastoma protein; p-Rb, phosphorylated Rb.
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f5-mmr-11-02-0924: EphA2 mediated paclitaxel sensitivity in NPC 5–8 cells via modulation of the PI3K/Akt signalling pathway. (A) PI3K/Akt signalling pathway inhibitor, LY294002, reverses paclitaxel resistance caused by EphA2 over-expression. (B) Effect of LY294002 on the cell-cycle distribution in EphA2 over-expressing NPC cells pre-treated with paclitaxel. (C) Effect of LY294002 on the apoptotic rate in NPC cells over-expressing EphA2, pretreated with paclitaxel. (D) LY294002 restores the changes in expression of cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1, caused by EphA2 over-expression. *P<0.05. EphA2, ephrin type-A receptor 2; NPC, nasopharyngeal carcinoma; PI3K, phosphoinositide 3-kinase; p-Akt, phsophorylated Akt; Rb, retinoblastoma protein; p-Rb, phosphorylated Rb.

Mentions: To further investigate the role of the PI3K/Akt signalling pathway in EphA2-mediated sensitivity to paclitaxel, a small molecule inhibitor of the PI3K/Akt signalling pathway, LY294002, was used to block this pathway in 5-8F cells over-expressing EphA2, and to observe whether EphA2-mediated changes in sensitivity to paclitaxel are reversed in EphA2-over-expressing 5-8F cells. As shown in Fig. 5A, LY294002 significantly restored sensitivity to paclitaxel, which had been reduced by EphA2 over-expression, in a dose-dependent manner. This was accompanied by corresponding changes in the cell-cycle phase distribution (Fig. 5B) but was not associated with changes in the percentage of apoptotic rate (Fig. 5C). Furthermore, the changes in expression of cell-cycle regulatory factors p21, p27 and p-Rb resulting from EphA2 over-expression were also reversed by the addition of LY294002 (Fig. 5D). These results provide further evidence that the PI3K/Akt pathway is involved in EphA2-mediated sensitivity to paclitaxel.


Ephrin type‑A receptor 2 regulates sensitivity to paclitaxel in nasopharyngeal carcinoma via the phosphoinositide 3‑kinase/Akt signalling pathway.

Wang Y, Liu Y, Li G, Su Z, Ren S, Tan P, Zhang X, Qiu Y, Tian Y - Mol Med Rep (2014)

EphA2 mediated paclitaxel sensitivity in NPC 5–8 cells via modulation of the PI3K/Akt signalling pathway. (A) PI3K/Akt signalling pathway inhibitor, LY294002, reverses paclitaxel resistance caused by EphA2 over-expression. (B) Effect of LY294002 on the cell-cycle distribution in EphA2 over-expressing NPC cells pre-treated with paclitaxel. (C) Effect of LY294002 on the apoptotic rate in NPC cells over-expressing EphA2, pretreated with paclitaxel. (D) LY294002 restores the changes in expression of cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1, caused by EphA2 over-expression. *P<0.05. EphA2, ephrin type-A receptor 2; NPC, nasopharyngeal carcinoma; PI3K, phosphoinositide 3-kinase; p-Akt, phsophorylated Akt; Rb, retinoblastoma protein; p-Rb, phosphorylated Rb.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4262504&req=5

f5-mmr-11-02-0924: EphA2 mediated paclitaxel sensitivity in NPC 5–8 cells via modulation of the PI3K/Akt signalling pathway. (A) PI3K/Akt signalling pathway inhibitor, LY294002, reverses paclitaxel resistance caused by EphA2 over-expression. (B) Effect of LY294002 on the cell-cycle distribution in EphA2 over-expressing NPC cells pre-treated with paclitaxel. (C) Effect of LY294002 on the apoptotic rate in NPC cells over-expressing EphA2, pretreated with paclitaxel. (D) LY294002 restores the changes in expression of cyclin-dependent kinase inhibitors, p21Cip1 and p27Kip1, caused by EphA2 over-expression. *P<0.05. EphA2, ephrin type-A receptor 2; NPC, nasopharyngeal carcinoma; PI3K, phosphoinositide 3-kinase; p-Akt, phsophorylated Akt; Rb, retinoblastoma protein; p-Rb, phosphorylated Rb.
Mentions: To further investigate the role of the PI3K/Akt signalling pathway in EphA2-mediated sensitivity to paclitaxel, a small molecule inhibitor of the PI3K/Akt signalling pathway, LY294002, was used to block this pathway in 5-8F cells over-expressing EphA2, and to observe whether EphA2-mediated changes in sensitivity to paclitaxel are reversed in EphA2-over-expressing 5-8F cells. As shown in Fig. 5A, LY294002 significantly restored sensitivity to paclitaxel, which had been reduced by EphA2 over-expression, in a dose-dependent manner. This was accompanied by corresponding changes in the cell-cycle phase distribution (Fig. 5B) but was not associated with changes in the percentage of apoptotic rate (Fig. 5C). Furthermore, the changes in expression of cell-cycle regulatory factors p21, p27 and p-Rb resulting from EphA2 over-expression were also reversed by the addition of LY294002 (Fig. 5D). These results provide further evidence that the PI3K/Akt pathway is involved in EphA2-mediated sensitivity to paclitaxel.

Bottom Line: In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5‑8F cells, compared with control cells exposed to the same concentrations of paclitaxel.Furthermore, paclitaxel stimulation and EphA2 over‑expression resulted in activation of the phosphoinositide 3‑kinase (PI3K)/Akt signalling pathway in NPC cells.The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Otolaryngology Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.

ABSTRACT
Ephrin type‑A receptor 2 (EphA2) is a receptor tyrosine kinase that is associated with cancer cell metastasis. There has been little investigation into its impact on the regulation of sensitivity to paclitaxel in nasopharyngeal carcinoma (NPC). In the present study, upregulation of EphA2 expression enhanced the survival of NPC 5‑8F cells, compared with control cells exposed to the same concentrations of paclitaxel. Flow cytometry and western blot analysis demonstrated that over‑expression of EphA2 decreased NPC cancer cell sensitivity to paclitaxel by regulating paclitaxel‑mediated cell cycle progression but not apoptosis in vitro. This was accompanied by alterations in the expression of cyclin‑dependent kinase inhibitors, p21 and p27, and of inactive phosphorylated‑retinoblastoma protein. Furthermore, paclitaxel stimulation and EphA2 over‑expression resulted in activation of the phosphoinositide 3‑kinase (PI3K)/Akt signalling pathway in NPC cells. Inhibition of the PI3K/Akt signalling pathway restored sensitivity to paclitaxel in 5‑8F cells over‑expressing EphA2, which indicated that the PI3K/Akt pathway is involved in EphA2‑mediated paclitaxel sensitivity. The current study demonstrated that EphA2 mediates sensitivity to paclitaxel via the regulation of the PI3K/Akt signalling pathway in NPC.

Show MeSH
Related in: MedlinePlus