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Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells.
Int J Mol Med 2015; 36(6):1556-62IJ

Abstract

There are numerous studies that demonstrate the anti-neoplastic activity of phosphatidylinositol 3-kinase (PI3K) inhibitors and the mechanisms of inducing autophagy in cancer cells. The new anticancer drug puquitinib mesylate (XC-302) is a molecular-targeted drug, which suppresses the activity of PI3K directly. However, it remains unclear whether XC‑302 can develop an antitumor effect by inducing autophagy in nasopharyngeal cancer cells. The MTT assay was used to study the anti-proliferative effects of XC-302. Subsequently, autophagy was determined by monodansylcadaverine (MDC) staining, punctate localization of green fluorescent protein (GFP)-light chain 3 (LC3), LC3 protein blotting and electron microscopy. The expression levels of beclin 1, p62, protein kinase B (AKT), phospho (p)‑AKT, mechanistic target of rapamycin (mTOR) and p‑mTOR in XC-302‑induced autophagy were detected. Autophagy inhibition was assayed by 3-methyladenine (3‑MA) or small interfering RNA (siRNA) silencing of beclin 1. XC-302 inhibited the viability of CNE‑2 in a dose-dependent manner and the IC50 of 72 h was 5.2 µmol/l. After cells were exposed to XC-302 for 24 h, MDC-labeled autophagolysosomes were evident in CNE-2 cells by fluorescence microscope. Autophagosomes and autolysosomes were identified by transmission electron microscopy. Following transfection with GFP‑LC3, XC-302 induced a significant accumulation of GFP‑LC3, as monitored by a confocal microscope, which was reduced by 3-MA. XC-302 induced the formation of LC3‑II, increased beclin 1 levels and decreased the expression of p62. Additionally, the expression levels of p‑AKT and p‑mTOR were reduced with the elevation of XC-302. Knockdown of beclin 1 with siRNA or co-treatment with 3-MA enhanced significantly the survival of CNE-2 and promoted the ability of clone formation. XC-302 also induced apoptosis in CNE-2, and when autophagy was inhibited by 3-MA, the apoptosis rate was decreased. The present data provides the evidence that XC-302 can induce autophagy in CNE-2, which promotes the program of cell death and inhibits the PI3K/AKT/mTOR signaling pathway. Furthermore, XC-302 also promoted apoptosis in CNE-2 cells, which could be reduced when autophagy was suppressed, meaning that autophagy may interact with apoptosis to induce cell death.

Authors+Show Affiliations

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26499488

Citation

Wang, Ke-Feng, et al. "Puquitinib Mesylate (XC-302) Induces Autophagy Via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Cancer Cells." International Journal of Molecular Medicine, vol. 36, no. 6, 2015, pp. 1556-62.
Wang KF, Yang H, Jiang WQ, et al. Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. Int J Mol Med. 2015;36(6):1556-62.
Wang, K. F., Yang, H., Jiang, W. Q., Li, S., & Cai, Y. C. (2015). Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. International Journal of Molecular Medicine, 36(6), pp. 1556-62. doi:10.3892/ijmm.2015.2378.
Wang KF, et al. Puquitinib Mesylate (XC-302) Induces Autophagy Via Inhibiting the PI3K/AKT/mTOR Signaling Pathway in Nasopharyngeal Cancer Cells. Int J Mol Med. 2015;36(6):1556-62. PubMed PMID: 26499488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Puquitinib mesylate (XC-302) induces autophagy via inhibiting the PI3K/AKT/mTOR signaling pathway in nasopharyngeal cancer cells. AU - Wang,Ke-Feng, AU - Yang,Hang, AU - Jiang,Wen-Qi, AU - Li,Su, AU - Cai,Yu-Chen, Y1 - 2015/10/16/ PY - 2015/04/01/received PY - 2015/10/05/accepted PY - 2015/10/27/entrez PY - 2015/10/27/pubmed PY - 2016/9/13/medline SP - 1556 EP - 62 JF - International journal of molecular medicine JO - Int. J. Mol. Med. VL - 36 IS - 6 N2 - There are numerous studies that demonstrate the anti-neoplastic activity of phosphatidylinositol 3-kinase (PI3K) inhibitors and the mechanisms of inducing autophagy in cancer cells. The new anticancer drug puquitinib mesylate (XC-302) is a molecular-targeted drug, which suppresses the activity of PI3K directly. However, it remains unclear whether XC‑302 can develop an antitumor effect by inducing autophagy in nasopharyngeal cancer cells. The MTT assay was used to study the anti-proliferative effects of XC-302. Subsequently, autophagy was determined by monodansylcadaverine (MDC) staining, punctate localization of green fluorescent protein (GFP)-light chain 3 (LC3), LC3 protein blotting and electron microscopy. The expression levels of beclin 1, p62, protein kinase B (AKT), phospho (p)‑AKT, mechanistic target of rapamycin (mTOR) and p‑mTOR in XC-302‑induced autophagy were detected. Autophagy inhibition was assayed by 3-methyladenine (3‑MA) or small interfering RNA (siRNA) silencing of beclin 1. XC-302 inhibited the viability of CNE‑2 in a dose-dependent manner and the IC50 of 72 h was 5.2 µmol/l. After cells were exposed to XC-302 for 24 h, MDC-labeled autophagolysosomes were evident in CNE-2 cells by fluorescence microscope. Autophagosomes and autolysosomes were identified by transmission electron microscopy. Following transfection with GFP‑LC3, XC-302 induced a significant accumulation of GFP‑LC3, as monitored by a confocal microscope, which was reduced by 3-MA. XC-302 induced the formation of LC3‑II, increased beclin 1 levels and decreased the expression of p62. Additionally, the expression levels of p‑AKT and p‑mTOR were reduced with the elevation of XC-302. Knockdown of beclin 1 with siRNA or co-treatment with 3-MA enhanced significantly the survival of CNE-2 and promoted the ability of clone formation. XC-302 also induced apoptosis in CNE-2, and when autophagy was inhibited by 3-MA, the apoptosis rate was decreased. The present data provides the evidence that XC-302 can induce autophagy in CNE-2, which promotes the program of cell death and inhibits the PI3K/AKT/mTOR signaling pathway. Furthermore, XC-302 also promoted apoptosis in CNE-2 cells, which could be reduced when autophagy was suppressed, meaning that autophagy may interact with apoptosis to induce cell death. SN - 1791-244X UR - https://www.unboundmedicine.com/medline/citation/26499488/Puquitinib_mesylate__XC_302__induces_autophagy_via_inhibiting_the_PI3K/AKT/mTOR_signaling_pathway_in_nasopharyngeal_cancer_cells_ L2 - http://www.spandidos-publications.com/ijmm/36/6/1556 DB - PRIME DP - Unbound Medicine ER -