Androgen Plays a Carcinogenic Role in EOC via the PI3K/AKT Signaling Pathway in an AR-Dependent Manner

Staurosporine, which is an inhibitor of a broad spectrum of protein kinases, has shown cytotoxicity on several human cancer cells. However, the underlying mechanism is not well understood. In this study, we examined whether and how this compound has an inhibitory action on phosphatidylinositol 3-kinase (PI3K)/Akt pathway in vitro using HepG2 human hepatocellular carcinoma cell line. Cell viability and apoptosis were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and terminal deoxyribonucleotidyl transferase–mediated dUTP-digoxigenin nick end labeling (TUNEL) assay, respectively. Glutathione S-transferase (GST) pull-down assay and co-immunoprecipitation were performed to detect protein–protein interactions. Small interfering RNA (siRNA) was used to silence the expression of targeted protein. We found that staurosporine significantly decreased cell viability and increased cell apoptosis in a concentration- and time-dependent manner in HepG2 cancer cells, along with the decreased expressions of PDK1 protein and Akt phosphorylation. Staurosporine was also found to enhance Omi/HtrA2 release from mitochondria. Furthermore, Omi/HtrA2 directly bound to PDK1. Pharmacological and genetic inhibition of Omi/HtrA2 restored protein levels of PDK1 and protected HepG2 cancer cells from staurosporine-induced cell death. In addition, staurosporine was found to activate autophagy. However, inhibition of autophagy exacerbated cell death under concomitant treatment with staurosporine. Taken together, our results indicate that staurosporine induced cytotoxicity response by inhibiting PI3K/Akt signaling pathway through Omi/HtrA2-mediated PDK1 degradation, and the process provides a novel mechanism by which staurosporine produces its therapeutic effects.

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Parthenolide Augments the Chemosensitivity of Non-small-Cell Lung Cancer to Cisplatin via the PI3K/AKT Signaling Pathway

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.610097 ◽

2021 ◽

Vol 8 ◽

Author(s):

Li-Mei Wu ◽

Xiao-Zhong Liao ◽

Yan Zhang ◽

Zi-Rui He ◽

Shi-Qing Nie ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Signaling Pathway ◽

Cell Lung Cancer ◽

Caspase 3 ◽

Akt Signaling ◽

Small Cell ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Small Cell Lung

The mortality rate of non-small-cell lung cancer (NSCLC) remains high worldwide. Although cisplatin-based chemotherapy may greatly enhance patient prognosis, chemotherapy resistance remains an obstacle to curing patients with NSCLC. Therefore, overcoming drug resistance is the main route to successful treatment, and combinatorial strategies may have considerable clinical value in this effort. In this study, we observed that both parthenolide (PTL) and cisplatin (DDP) inhibited the growth of NSCLC cells in a dose- and time-dependent manner. The combination of PTL and DDP presented a synergistic inhibitory effect on NSCLC at a ratio of 50:1. The combination of PTL and DDP synergistically inhibited cell migration and invasion, inhibited cell cycle progression, and induced apoptosis of A549 and PC9 cells. Bioinformatics and network pharmacology analysis indicated that PTL may primarily affect the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway. After treatment with PTL and DDP either alone or in combination, Western blot analysis revealed that the proteins levels of Bax and cleaved Caspase-3 were upregulated, while p-PI3K, p-Akt, Caspase-3, and Bcl-2 proteins were downregulated. Among these alterations, the combination of PTL and DDP was found to exhibit the most significant effects. PTL might therefore be considered as a new option for combination therapy of NSCLC.

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Effect of Eriodictyol on Retinoblastoma via the PI3K/Akt Pathway

Journal of Healthcare Engineering ◽

10.1155/2021/6091585 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Shu Wen ◽

Meng Hu ◽

Yan Xiong

Keyword(s):

Anticancer Activity ◽

Signaling Pathway ◽

Vision Loss ◽

Akt Signaling ◽

Migration And Invasion ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Anticancer Effects ◽

Induced Apoptosis ◽

Y79 Cells

Retinoblastoma (RB) is one of the most common intraocular malignancies in children, which causes vision loss and even threatens life. Eriodictyol is a natural flavonoid with strong anticancer activity. Some studies have shown that eriodictyol exerts anticancer effects in glioma, colon cancer, and lung cancer; however, no studies have reported the anticancer effects of eriodictyol on RB. Therefore, the aim of this study was to investigate the anticancer activity of eriodictyol against the RB Y79 cell line and its potential mechanism of action. Interestingly, we found that eriodictyol inhibited the proliferation, migration, and invasion of Y79 cells in a dose-dependent manner and decreased the expression of MMP-2 and MMP-9 proteins in the cells. In addition, eriodictyol-induced apoptosis in Y79 cells was assessed by flow cytometry and immunoblotting. Here, our study revealed that eriodictyol dose dependently inhibited the activation of the PI3K/Akt signaling pathway. Notably, the effect of eriodictyol on RB apoptosis was reversed by a PI3K agonist 740 Y-P. In conclusion, our study shows that eriodictyol effectively inhibits proliferation, migration, and invasion and induces apoptosis in RB cell lines, which may be the result of blocking the PI3K/Akt signaling pathway. Thus, eriodictyol may provide a new theoretical basis for exploring targeted antitumor natural therapies.

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Effects of Rhizopus Nigricans Exopolysaccharide on Proliferation, Apoptosis, and Migration of Breast Cancer MCF-7 Cells and Akt Signaling Pathway

International Journal of Polymer Science ◽

10.1155/2021/5621984 ◽

2021 ◽

Vol 2021 ◽

pp. 1-6

Author(s):

Aizhai Xiang ◽

Chen Ling ◽

Wei Zhang ◽

Honggang Chen

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Akt Signaling ◽

Migration And Invasion ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Rhizopus Nigricans ◽

And Migration ◽

The Impact ◽

Mcf 7

Objective. To study the effect of Rhizopus nigricans exopolysaccharide EPS1-1 on the proliferation, apoptosis, and migration of breast cancer MCF-7 cells. Methods. Human breast cancer MCF-7 cells were cultured in vitro and treated with different concentrations of EPS1-1. The effect of EPS1-1 on cell proliferation was tested by the CCK-8 experiment, and the effect of EPS1-1 on cell apoptosis was determined by flow cytometry. And the scratch test was used to detect the impact of EPS1-1 on cell migration. Western blot then was used to measure the expression changes of related proteins in the Akt signaling pathway. Results. Compared with the control group, treatment with EPS1-1 significantly reduced the proliferation, migration, and invasion ability of MCF-7 cells and promoted the apoptosis of MCF-7 cells in a dose-dependent manner. In terms of the underlying mechanism, EPS1-1 can significantly inhibit the phosphorylation of Akt at threonine 308 and serine 473 and cause the expression changes of downstream proliferation-related genes CCND1 and p21, apoptosis-related genes Bcl-2 and Bax, and migration-related genes Vimentin and E-cadherin in terms of their protein levels. Conclusion. EPS1-1 can inhibit the proliferation, migration, and invasion of breast cancer MCF-7 cells and promote the apoptosis of MCF-7 cells by inhibiting the activation of the Akt signaling pathway. Therefore, EPS1-1 can be used as a potential new drug or adjuvant drug for the treatment of breast cancer.

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Dehydrocostus Lactone Inhibits Proliferation, Antiapoptosis, and Invasion of Cervical Cancer Cells Through PI3K/Akt Signaling Pathway

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000474 ◽

2015 ◽

Vol 25 (7) ◽

pp. 1179-1186 ◽

Cited By ~ 12

Author(s):

Enping Jiang ◽

Xiwen Sun ◽

Haixian Kang ◽

Liping Sun ◽

Weifang An ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Specific Inhibitor ◽

Akt Signaling ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Cervical Cancer Cells ◽

Dehydrocostus Lactone

ObjectivesRecent studies found that dehydrocostus lactone (DHC), a traditional Chinese medicine in curing chronic ulcer and inflammation, can inhibit several type of tumor cells. The purpose of this study was to define the role of DHC on cervical cancer cells and to explore its mechanism of action.MethodsWe used DHC alone or in combination with PI3K/Akt-specific inhibitor LY294002 (LY) to treat Hela cells [human papillomavirus (HPV)-18 positive] and C33a cells (HPV negative). The proliferation, apoptosis, and Akt activation were assessed. Cell invasive ability was assayed in transwell chambers.ResultsWe found that DHC significantly inhibited proliferation, antiapoptosis, and invasion of both cells, and reduced the level of p-Akt phosphorylation in these cells, in a dose- or time-dependent manner. In addition, these inhibitions of DHC were significantly strengthened by LY.ConclusionsThe result suggested that DHC plays a potent role in anticervical cancer in multiple biological aspects through PI3K/Akt signaling pathway, independently of HPV infection. This finding surely adds new knowledge to understand the role of DHC in fighting cancers.

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Docetaxel Combined with Thymoquinone Induces Apoptosis in Prostate Cancer Cells via Inhibition of the PI3K/AKT Signaling Pathway

Cancers ◽

10.3390/cancers11091390 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1390 ◽

Cited By ~ 8

Author(s):

Santosh Kumar Singh ◽

Tejumola Apata ◽

Jennifer B. Gordetsky ◽

Rajesh Singh

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Signaling Pathway ◽

Akt Signaling ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Concentration Dependent Manner ◽

Development Of Resistance ◽

Synergistic Cytotoxicity ◽

The Individual

Toxicity and the development of resistance by cancer cells are impediments for docetaxel (DTX), a primary drug for treating prostate cancer (PCa). Since the combination of DTX with natural compounds can increase its effectiveness by reducing its toxic concentrations, we evaluated a combination of thymoquinone (TQ) with DTX and determined its cytotoxicity against PCa cells (DU145 and C4-2B). This combination, in a concentration-dependent manner, resulted in synergistic cytotoxicity and apoptosis in comparison to either DTX or TQ alone. In addition, inhibition of cell survival pathways by PI3K/AKT inhibitors conferred sensitivity of DU145 and C4-2B cells to the combination as compared to the individual drugs. Moreover, the combined drugs (DTX+TQ) with inhibitors of PI3K/AKT increased the expression of pro-apoptotic markers (BAX and BID) along with caspase-3, PARP and decreased expression of the anti-apoptotic marker, BCL-XL. These data show that, for PCa cells, the cytotoxic effect of the DTX and TQ combination correlates with a block of the PI3K/AKT signaling pathway. These findings indicate that the combination of DTX and TQ, by blocking of the PI3K/AKT pathway, will improve the survival rate and quality of life of PCa patients.

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Carbamylated erythropoietin regulates immune responses and promotes long-term kidney allograft survival through activation of PI3K/AKT signaling

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00232-5 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Ning Na ◽

Daqiang Zhao ◽

Jinhua Zhang ◽

Jiaqing Wu ◽

Bin Miao ◽

...

Keyword(s):

Immune Responses ◽

Signaling Pathway ◽

Immune Cells ◽

Akt Signaling ◽

Control Group ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Allograft Survival ◽

Kidney Allograft

Abstract Modulation of alloimmune responses is critical to improving transplant outcome and promoting long-term graft survival. To determine mechanisms by which a nonhematopoietic erythropoietin (EPO) derivative, carbamylated EPO (CEPO), regulates innate and adaptive immune cells and affects renal allograft survival, we utilized a rat model of fully MHC-mismatched kidney transplantation. CEPO administration markedly extended the survival time of kidney allografts compared with the transplant alone control group. This therapeutic effect was inhibited when the recipients were given LY294002, a selective inhibitor of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway or anti-EPO receptor (EPOR) antibody, in addition to CEPO. In vitro, CEPO inhibited the differentiation and function of dendritic cells and modulated their production of pro-inflammatory and anti-inflammatory cytokines, along with activating the PI3K/AKT signaling pathway and increasing EPOR mRNA and protein expression by these innate immune cells. Moreover, after CD4+ T cells were exposed to CEPO the Th1/Th2 ratio decreased and the regulatory T cell (Treg)/Th17 ratio increased. These effects were abolished by LY294002 or anti-EPOR antibody, suggesting that CEPO regulates immune responses and promotes kidney allograft survival by activating the PI3K/AKT signaling pathway in an EPOR-dependent manner. The immunomodulatory and specific signaling pathway effects of CEPO identified in this study suggest a potential therapeutic approach to promoting kidney transplant survival.

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MicroRNA-26a inhibits wound healing through decreased keratinocytes migration by regulating ITGA5 through PI3K/AKT signaling pathway

Bioscience Reports ◽

10.1042/bsr20201361 ◽

2020 ◽

Vol 40 (9) ◽

Author(s):

Zhongping Jiang ◽

Jie Wei ◽

Weize Yang ◽

Wen Li ◽

Feng Liu ◽

...

Keyword(s):

Wound Healing ◽

Protein Expression ◽

Signaling Pathway ◽

Akt Signaling ◽

Luciferase Reporter ◽

Epidermal Keratinocytes ◽

Dependent Manner ◽

Hacat Cells ◽

Akt Signaling Pathway ◽

Tgf Β1

Abstract Background: Keratinocyte migration is essential for skin wound healing and recent studies demonstrated that microRNAs (miRNAs) are involved in the differentiation, migration and apoptosis in keratinocytes. However, the function of miR-26a in wound healing remains to be largely explored. Methods: Northern blot and quantitative reverse transcriptase PCR (qRT-PCR) were used to detect the miR-26a expression and Western blot was used to detect integrin α-5 (ITGA5), phosphatidylinositol-3-kinase (PI3K), p-PI3K, protein kinase B (AKT) and p-AKT protein expression in immortalized human keratinocyte cell line HaCaT and normal human epidermal keratinocytes (NHEK) after 2 ng/ml transforming growth factor-β1 (TGF-β1) treatment for 0, 6, 12 and 24 h. Transwell assay and Wound healing assay were introduced to measure the cell migration of HaCaT cells. TargetScan online database, luciferase reporter assay and RNA immunoprecipitation (RIP) were employed to confirm the relationship between miR-26a and ITGA5. Results: The RNA expression of miR-26a was down-regulated and ITGA5 protein expression was up-regulated by TGF-β1 treatment in HaCaT and NHEK cells in a time-dependent manner. MiR-26a overexpression inhibited the migration of HaCaT cells induced by TGF-β1 while miR-26a inhibitor enhanced the migration. ITGA5 was a downstream target mRNA and regulated by miR-26a. ITGA5 overexpression reversed the inhibitory effect of miR-26a on migration in HaCaT, while ITGA5 knockdown attenuated the stimulative effect of miR-26a inhibitor in HaCaT via PI3K/AKT signaling pathway. Conclusion: MiR-26a overexpression inhibited TGF-β1 induced HaCaT cells migration via down-regulating ITGA5 through activating the PI3K/AKT signaling pathway.

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Taurine attenuates acrylamide-induced apoptosis via a PI3K/AKT-dependent manner

Human & Experimental Toxicology ◽

10.1177/0960327118765335 ◽

2018 ◽

Vol 37 (12) ◽

pp. 1249-1257 ◽

Cited By ~ 6

Author(s):

G Sun ◽

X Wang ◽

T Li ◽

S Qu ◽

J Sun

Keyword(s):

Signaling Pathway ◽

Akt Signaling ◽

Terminal Deoxynucleotidyl Transferase ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Akt Inhibitor ◽

Higher Temperature ◽

Induced Apoptosis

As a potent neurotoxic agent, acrylamide (ACR) is formed in food processing at higher temperature. Taurine (TAU), a nonessential amino acid, is used to cure neurodegenerative disorders, followed by activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. In this article, we certified that antiapoptotic efficacy of TAU in vivo and vitro. ACR-treated rats received TAU by drinking water 2 weeks after ACR intoxication. The results showed that in treated rats, TAU alleviated ACR-induced neuronal apoptosis, which was associated with the activation of PI3K/AKT signaling pathway. TAU attenuated apoptosis caused by ACR through observing terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, measure of protein expression of Bcl-2, Bax, and caspase 3 activity. TAU-induced antiapoptotic effect is PI3K/AKT-dependent, which was proved in ACR-intoxicated ventral spinal cord 4.1 cells in the presence of AKT inhibitor, MK-2206. Therefore, our results demonstrated that TAU-attenuated ACR-induced apoptosis in vivo through a PI3K/AKT-dependent manner provided new sights in the molecular mechanism of TAU protection against ACR-induced neurotoxicity.

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Eriodictyol Suppresses Survival of Cervical Cancer Cells Through Mediation of PTEN/Akt Signaling Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.18:196-200 ◽

2019 ◽

Vol 18 (2) ◽

pp. 196-200

Author(s):

Yu Lixiao ◽

Liu Xiaoyun

Keyword(s):

Cell Cycle ◽

Cervical Cancer ◽

Cell Survival ◽

Cancer Cells ◽

Signaling Pathway ◽

Hela Cells ◽

Akt Signaling ◽

Dependent Manner ◽

Akt Signaling Pathway ◽

Cervical Cancer Cells

Cervical cancer is one of the most malignant cancers of the female reproductive system with high morbidity and mortality. In the current study, we have examined the effect of eriodictyol on cell survival including cell growth, cell cycle and apoptosis of cervical cancer cells and also explored the underlying mechanism(s). To this end, CCK-8 assay, flow cytometry and western blotting assays were performed in cervical cancer HeLa cells. Eriodictyol significantly inhibited cell survival including impeding the cell viability, arresting the cell cycle at the G1 phase and potentiating cell apoptosis in a concentration-dependent manner. Also, ERI activated PTEN, P21, cleaved caspase-3/-9 expression and downregulated P-Akt and cyclin D1 expression in a dose-dependent manner. In conclusion, ERI can inhibit cervical cancer HeLa cells viability via impeding cell cycle and inducing apoptosis by regulating PTEN/Akt signaling pathway.

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