Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway

Jin, Yingying; Xu, Kun; Chen, Qingjuan; Wang, Baofeng; Pan, Jiyuan; Huang, Shan; Yang, Wei; Ma, Hongbing

doi:10.1016/j.yexcr.2017.11.037

Cited by 39 publications

(30 citation statements)

References 31 publications

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“…Recently, it was reported that simvastatin had a therapeutic effect in several cancers. The administration of simvastatin suppressed EMT through the phosphatase and tensin homologue (PTEN)/PI3K/Akt pathway in EC9706‐R cells, suggesting a new therapeutic function for simvastatin in cancers . Trichostatin A, a histone deacetylase inhibitor, is an antifungal antibiotic.…”

Section: Small Molecules Against Emtmentioning

confidence: 95%

“…The administration of simvastatin suppressed EMT through the phosphatase and tensin homologue (PTEN)/PI3K/Akt pathway in EC9706-R cells, suggesting a new therapeutic function for simvastatin in cancers. 34 Trichostatin A, a histone deacetylase inhibitor, is an antifungal antibiotic. In addition to its antibiotic properties, trichostatin A alleviated EMT in bleomycininduced lung injury in mice via inhibiting the Akt signaling pathway.…”

Section: Akt Signaling Pathwaymentioning

confidence: 99%

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Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

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Tissue fibrosis and cancer both lead to high morbidity and mortality worldwide; thus, effective therapeutic strategies are urgently needed. Because drug resistance has been widely reported in fibrotic tissue and cancer, developing a strategy to discover novel targets for targeted drug intervention is necessary for the effective treatment of fibrosis and cancer. Although many factors lead to fibrosis and cancer, pathophysiological analysis has demonstrated that tissue fibrosis and cancer share a common process of epithelial‐mesenchymal transition (EMT). EMT is associated with many mediators, including transcription factors (Snail, zinc‐finger E‐box‐binding protein and signal transducer and activator of transcription 3), signaling pathways (transforming growth factor‐β1, RAC‐α serine/threonine‐protein kinase, Wnt, nuclear factor‐kappa B, peroxisome proliferator‐activated receptor, Notch, and RAS), RNA‐binding proteins (ESRP1 and ESRP2) and microRNAs. Therefore, drugs targeting EMT may be a promising therapy against both fibrosis and tumors. A large number of compounds that are synthesized or derived from natural products and their derivatives suppress the EMT by targeting these mediators in fibrosis and cancer. By targeting EMT, these compounds exhibited anticancer effects in multiple cancer types, and some of them also showed antifibrotic effects. Therefore, drugs targeting EMT not only have both antifibrotic and anticancer effects but also exert effective therapeutic effects on multiorgan fibrosis and cancer, which provides effective therapy against fibrosis and cancer. Taken together, the results highlighted in this review provide new concepts for discovering new antifibrotic and antitumor drugs.

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Section: Small Molecules Against Emtmentioning

confidence: 95%

Section: Akt Signaling Pathwaymentioning

confidence: 99%

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Feng

Chen

Vaziri

et al. 2019

Medicinal Research Reviews

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“…It has been reported that RR is acquired in various cancer types, including head and neck cancer, non-small cell lung cancer, breast cancer and PCa (8)(9)(10)(11). RR cells demonstrate resistance to the induction of apoptosis, decreased production of reactive oxygen species (ROS) (12), increased activation of DNA repair (13), and exhibit high migratory and invasive abilities (14). RR PCa cells exhibit a number of features, including an increase in the number of cancer stem cells (CSCs) (15)(16)(17), increased neuroendocrine differentiation (NED) (18)(19)(20) and increased epithelial-mesenchymal transition (15,16).…”

Section: Introductionmentioning

confidence: 99%

“…Cancer cells acquire RR by fractionated irradiation, and certain features of RR cells have been described (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). However, to the best of our knowledge, the mechanism underlying RR acquisition during fractionated irradiation is unclear.…”

Section: Introductionmentioning

confidence: 99%

Understanding the mechanism underlying the acquisition of radioresistance in human prostate cancer cells

et al. 2019

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Acquisition of radioresistance (RR) has been reported during cancer treatment with fractionated irradiation. However, RR is poorly understood in the prognosis of radiotherapy. Although radiotherapy is important in the treatment of prostate cancer (PCa), acquisition of RR has been reported in PCa with an increased number of cancer stem cells (CSCs), neuroendocrine differentiation (NED) and epithelial-mesenchymal transition. However, to the best of our knowledge, the mechanism underlying RR acquisition during fractionated irradiation remains unclear. In the present study, human PCa cell lines were subjected to fractionated irradiation according to a fixed schedule as follows: Irradiation (IR)1, 2 Gy/day with a total of 20 Gy; IR2, 4 Gy/day with a total of 20 Gy; and IR3, 4 Gy/day with a total of 56 Gy. The expression of cluster of differentiation (CD)44, a CSC marker, was identified to be increased by fractionated irradiation, particularly in DU145 cells. The expression levels of CD133 and CD138 were increased compared with those in parental cells following a single irradiation or multiple irradiations; however, the expression levels decreased with subsequent irradiation. RR was evidently acquired by exposure to 56 Gy radiation, which resulted in increased expression of the NED markers CD133 and CD138, and increased mRNA expression levels of the pluripotency-associated genes octamer-binding transcription factor 4 and Nanog homeobox. These data indicate that radiation-induced CSCs emerge due to the exposure of cells to fractionated irradiation. In addition, the consequent increase in the expression of NED markers is possibly induced by the increased expression of pluripotency-associated genes. Therefore, it can be suggested that cancer cells acquire RR due to increased expression of pluripotency-associated genes following exposure to fractionated irradiation.

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“…The aforementioned results demonstrate that activated AKT can promote EMT and induce tumor formation and metastasis. Jin et al (29) also indicated that inhibition of the PTEN/PI3K/AKT signaling pathway can enhance the sensitivity of esophageal cancer to radiotherapy and reverse the process of EMT. This studied showed that the upregulation of PTEN expression and inhibition of AKT phosphorylation can promote esophageal cancer cell apoptosis, enhance the expression of E-cadherin and downregulate the expression of N-cadherin and vimentin to inhibit cancer cell invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Role and mechanism of PTEN in Burkitt's lymphoma

Xin

et al. 2020

Oncol Rep

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The aim of the present study was to explore the possible mechanisms of phosphatase and tensin homolog (PTEN) in the pathogenesis of Burkitt's lymphoma, and provide novel information that can be used in the targeted treatment of this disease. PTEN lentiviral overexpression vector and short-hairpin PTEN silencing vectors were constructed. The effect of PTEN on the growth and proliferation of CA46 and RAJI cells was analyzed using a Cell Counting Kit-8 assay. Apoptosis was detected by Hoechst 33342 and propidium iodide double staining. Flow cytometry was used to analyze the cell cycle. A Transwell chamber was used to detect cell migration and invasion abilities. Western blot analysis was used to detect related protein changes. The mechanism of the effect of PTEN on the biological characteristics of Burkitt's lymphoma cells was subsequently analyzed. The results revealed that PTEN inhibited the proliferation of CA46 and RAJI cells by downregulating the expression of p-AKT, It was indicated that the upregulation of proapoptotic proteins (including Bad and Bax) induced apoptosis, regulated cyclin (including P53, P21, CDK4, CDK6, cyclin D3 and cyclin H) to inhibit cell cycle progression, and mediated epithelial-mesenchymal transition-like cell markers (including E-cadherin, N-cadherin, β-catenin, TCF-8, vimentin, Slug and Snail) to inhibit cell migration and invasion. In conclusion, the tumor-suppressor gene PTEN inhibited the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibited the proliferation and migration of Burkitt's lymphoma cells, induced apoptosis and cell cycle arrest, thus playing a crucial role in the pathogenesis of Burkitt's lymphoma.

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Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway

Cited by 39 publications

References 31 publications

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

Understanding the mechanism underlying the acquisition of radioresistance in human prostate cancer cells

Role and mechanism of PTEN in Burkitt's lymphoma

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