Dual blocking of PI3K and mTOR signaling by NVP-BEZ235 inhibits proliferation in cervical carcinoma cells and enhances therapeutic response

Xie, Guifang; Wang, Zhaoyong; Chen, Yong; Zhang, Shuya; Lu, Feng; Meng, Fanhui; Yu, Zhiyun

doi:10.1016/j.canlet.2016.11.024

Cited by 33 publications

(28 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accumulating preclinical studies have demonstrated that NVP-BEZ235 has beneficial pharmaceutical properties as an anticancer agent. It was previously reported that NVP-BEZ235 exhibited promising therapeutic activity in various types of cancer when used alone or combined with agents other than DDP (25,30). In the present study, BEZ235 also demonstrated strong antitumor activity in MTT assays.…”

Section: Discussionsupporting

confidence: 72%

See 1 more Smart Citation

Co-treatment with BEZ235 enhances chemosensitivity of A549/DDP cells to cisplatin via inhibition of PI3K/Akt/mTOR signaling and downregulation of ERCC1 expression

Xia

et al. 2018

Oncol Rep

View full text Add to dashboard Cite

The activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling and upregulation of excision repair cross complementation group 1 (ERCC1) are the two most important factors that confer resistance to cisplatin (DDP) therapy in non-small-cell lung cancer (NSCLC). Therefore, inhibition of the PI3K/Akt/mTOR signaling pathway and ERCC1 expression is a potential approach for the treatment of patients with advanced NSCLC. In the present study, whether combined treatment with DDP and BEZ235, a dual PI3K/mTOR inhibitor, could provide a synergistic antitumor effect in A549/DDP cells was investigated, and the possible mechanisms involved were explored. The half-maximal inhibitory concentration (IC50) values were calculated in A549/DDP cells. Synergistic interaction of BEZ235 and DDP was evaluated by combination index (CI) analysis. The levels of phosphorylated Akt (p-Akt), phosphorylated mTOR (p-mTOR), apoptosis-related proteins and ERCC1 were detected by western blot analysis. Apoptotic cells were quantified by flow cytometry and Hoechst 33342 staining. The migration and invasion abilities of A549/DDP cells were evaluated by wound healing and Transwell assays, respectively. It was observed that the dose reduction index (DRI) of BEZ235 was 13.82 and for DDP it was 13.58, and the CI of combination was <1 over a wide range of doses. In addition, the levels of p-Akt, p-mTOR and ERCC1 were significantly elevated by DDP treatment, and were reduced by co-administration of BEZ235 and DDP. Furthermore, the combination treatment significantly induced apoptotic cell death, decreased migration and invasion abilities compared with those treated with either BEZ235 or DDP alone. In conclusion, the combination of BEZ235 with DDP had synergistic antitumor effects in A549/DDP cells as reflected by reduced proliferation, increased apoptosis, and suppression of the migration and invasion abilities of A549/DDP cells, and the mechanism mediating these effects may be associated with the inhibition of PI3K/Akt/mTOR signaling and down-regulation of ERCC1 expression.

show abstract

Section: Discussionsupporting

confidence: 72%

“…BEZ235, a novel dual PI3K/mTOR inhibitor, can reverse the hyperactivation of the PI3K/Akt/mTOR pathway, resulting in antitumor activity in cancer of various origins (23)(24)(25). Recently, studies have revealed that combined treatment with AZD6244, Trichostatin A and BEZ235 exerted synergistic antitumor effects on NSCLC cells (26,27).…”

Section: Introductionmentioning

confidence: 99%

Co-treatment with BEZ235 enhances chemosensitivity of A549/DDP cells to cisplatin via inhibition of PI3K/Akt/mTOR signaling and downregulation of ERCC1 expression

Xia

et al. 2018

Oncol Rep

View full text Add to dashboard Cite

show abstract

“…In clinical trials, PI3K/AKT/mTOR inhibitors have been used as molecular targeted therapies in cervical cancer, and the PI3K/AKT inhibitor, LY294002 was found to increase radiation sensitivity in cervical cancer cell lines (45). The PI3K/mTOR inhibitor, NVP-BEZ235, was also found to exert an effect on cervical cancer cells (46). Recent research has revealed that Akt/mTOR signaling promotes neuroendocrine cervical cancer, which has an extremely poor prognosis, suggesting that this pathway may be utilized for novel anticancer treatment strategies (47).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑126‑3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K/PDK1/AKT pathway

et al. 2020

View full text Add to dashboard Cite

We previously reported that relative to normal cervical mucus, microRNA 126-3p (miR-126-3p) is present in significantly greater amounts in the cervical mucus of patients with overt cervical cancer or precursor lesions. Here, we investigated the effects of enforced miR-126-3p expression in the cervical cancer cell line, HeLa, on proliferation, migration, invasion, apoptosis and protein expression. We transfected HeLa cells with miR-126-3p miRNA and found that proliferation, migration and invasion by cell counting, wound healing, cell migration and invasion assay were significantly reduced in these cells relative to those transfected with a negative control mimic. The levels of phosphoinositide 3 kinase (PI3K), phosphorylated 3-phosphoinositide-dependent protein kinase-1 (p-PDK1) and p-AKT proteins were lower in the miR-126-3p-transfected cells. Phosphorylated 70S6K (p-p70S6K), phosphorylated glycogen synthase kinase 3β (p-GSK3β), phosphorylated S6K (p-S6K), cyclin D1, phosphorylated p21-activated kinase 1 (p-PAK1), Rho associated coiled-coil containing protein kinase 1 (ROCK1), myotonic dystrophy-related CDC42-binding kinases α (MRCKα) and phospholipase C γ1 (p-PLCγ1) were also downregulated. This suggests that downstream effectors of the PI3K/PDK1/AKT pathway are targets for inhibition by miR-126-3p. In contrast, apoptotic-related proteins including the BCL-2-associated agonist of cell death (Bad), B-cell lymphoma-extra-large (Bcl-xL) and BCL-2-associated X (Bax), were all upregulated by miR-126-3p, resulting in increased caspase 3/7 activity and apoptosis. Thus, enforced expression of miR-126-3p inhibited cell migration and invasion and also induced apoptosis by regulating the PI3K/PDK1/AKT pathway in HeLa cells. Hence, high levels of miR-126-3p may inhibit cervical carcinogenesis, and targeting the PI3K/PDK1/AKT pathway via miR-126-3p could represent a new approach for treating patients with cervical cancer.

show abstract

“…Therefore, novel and effective therapeutic strategies for cervical cancer are urgently required. Accumulating evidence has indicated that the development of cervical cancer is a multi-step process, including the abnormal expression of oncogenes and tumor suppressor genes (5)(6)(7). Despite advances in cervical cancer, the precise molecular mechanisms of carcinogenesis and progression underlying cervical cancer are only partly understood (5).…”

Section: Introductionmentioning

confidence: 99%

Upregulation and hypomethylation of lncRNA AFAP1‑AS1 predicts a poor prognosis and promotes the migration and invasion of cervical cancer

Fan

Gong

et al. 2019

Oncol Rep

View full text Add to dashboard Cite

Although lncRNA AFAP1 antisense RNA1 (AFAP1-AS1) is considered an oncogenic lncRNA, little is known about the role of AFAP1-AS1 in cervical cancer. In the present study, we found that AFAP1-AS1 was elevated and hypomethylated in cervical cancer and was associated with a poor prognosis of patients with cervical cancer by analyzing the Cancer RNA-Seq Nexus (CRN), MethCH and UCSC XENA databases. Subsequently, we knocked AFAP1-AS1 expression down using siRNAs in cervical cancer cells. Wound healing experiments and matrigel invasion experiments revealed that the downregulation of AFAP1-AS1 suppressed the migration and invasion of cervical cancer cells. Furthermore, western blot analysis demonstrated that the antitumor effects induced by the silencing of AFAP1-AS1 were mainly mediated through the regulation of the Rho/Rac signaling pathway and epithelial-mesenchymal transition (EMT)-related genes. Taken together, the findings of the present study indicate that the expression level of AFAP1-AS1 may be involved in the development of cervical cancer. Thus, AFAP1-AS1 may be a novel prognostic biomarker and a potential therapeutic target for patients with cervical cancer.

show abstract

Dual blocking of PI3K and mTOR signaling by NVP-BEZ235 inhibits proliferation in cervical carcinoma cells and enhances therapeutic response

Cited by 33 publications

References 27 publications

Co-treatment with BEZ235 enhances chemosensitivity of A549/DDP cells to cisplatin via inhibition of PI3K/Akt/mTOR signaling and downregulation of ERCC1 expression

Co-treatment with BEZ235 enhances chemosensitivity of A549/DDP cells to cisplatin via inhibition of PI3K/Akt/mTOR signaling and downregulation of ERCC1 expression

MicroRNA‑126‑3p suppresses HeLa cell proliferation, migration and invasion, and increases apoptosis via the PI3K/PDK1/AKT pathway

Upregulation and hypomethylation of lncRNA AFAP1‑AS1 predicts a poor prognosis and promotes the migration and invasion of cervical cancer

Contact Info

Product

Resources

About