Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis

Yang, Fen; Tang, Xiao Yan; Líu, Hao; Zao, Jiang

doi:10.3892/or.2016.4580

Cited by 19 publications

(17 citation statements)

References 29 publications

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“…To quantify Ki67 expression, both the intensity and extent of immunoreactivity were evaluated and scored. IHC staining and score evaluation were performed according to standard protocols as described previously [ 25 ].…”

Section: Methodsmentioning

confidence: 99%

STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy

et al. 2018

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BackgroundLong noncoding RNAs (lncRNAs) are an important class of functional regulators involved in human cancers development, including gastric cancer (GC). Studying aberrantly expressed lncRNAs may provide us with new insights into the occurrence and development of gastric cancer by acting as oncogenes or tumor suppressors. In this study, we aim to examine the expression pattern of lncRNA HAGLROS in GC and its clinical significance as well as its biological role in tumor progression.MethodsBioinformatics analysis and qRT-PCR were performed to detect the relative expression of HAGLROS in GC tissues and cell lines. Gain or loss of function approaches were used to investigate the biological functions of HAGLROS. The effect of HAGLROS on proliferation was evaluated by MTT, colony formation assay and nude mouse xenograft model. Wound healing and Transwell assays were used to study the invasion and migration of GC cells. FISH, RIP, RNA-seq, Luciferase report assays, RNA pulldown and Western blot were fulfilled to measure molecular mechanisms. Results are shown as means ± S.D. and differences were tested for significance using Student’s t-test (two-tailed).ResultsWe screened out HAGLROS, whose expression was significantly increased and correlated with outcomes of GC patients by publicly available lncRNAs expression profiling and integrating analyses. Exogenous down-regulation of HAGLROS expression significantly suppressed the cell proliferation, invasion and migration. Mechanistic investigations showed that HAGLROS was a direct target of transcriptional factor STAT3. Moreover, HAGLROS knockdown decreased mTOR expression and increased autophagy-related genes ATG9A and ATG9B expression. Further investigation showed that HAGLROS regulated mTOR signals in two manners. In the one hand, HAGLROS competitively sponged miR-100-5p to increase mTOR expression by antagonizing miR-100-5p-mediated mTOR mRNA inhibition. On the other hand, HAGLROS interacted with mTORC1 components to activate mTORC1 signaling pathway which was known to be an important negative signal of autophagy. Here activation of mTORC1 signaling pathway by HAGLROS inhibited autophagy, thereby promoted excessive proliferation and maintained the malignant phenotype of GC cells.ConclusionThe present study demonstrates that HAGLROS overexpression contributes to GC development and poor prognosis and will be a target for GC therapy and further develop as a potential prognostic biomarker.Electronic supplementary materialThe online version of this article (10.1186/s12943-017-0756-y) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy

et al. 2018

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“…19 Targeting at the PI3K/ AKT/mTOR signaling pathway, a dual PI3K/mTOR inhibitor, BEZ235, was developed to inhibit tumor growth, 20 the mechanism of which might be partially attributed to phosphorylation of relevant proteins in the PI3K/AKT/mTOR signaling pathway. 19 Yang et al 21 have reported that PI3K/AKT signaling pathway, one of the survival signaling pathways, plays an important role in resisting the apoptosis-inducing ability of ERS. Moreover, it has been proved that BEZ235 inhibited MCF-7 cell proliferation via the PI3K/AKT/mTOR signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

Zhong

Wang

et al. 2017

Tumour Biol.

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Nowadays, although chemotherapy is an established therapy for breast cancer, the molecular mechanisms of chemotherapy resistance in breast cancer remain poorly understood. This study aims to explore the effects of endoplasmic reticulum stress on autophagy, apoptosis, and chemotherapy resistance in human breast cancer cells by regulating PI3K/AKT/mTOR signaling pathway. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the cell viability of six human breast cancer cell lines (MCF-7, ZR-75-30, T47D, MDA-MB-435s, MDA-MB-453, and MDA-MB-231) treated with tunicamycin (5 µM), after which MCF-7 cells were selected for further experiment. Then, MCF-7 cells were divided into the control (without any treatment), tunicamycin (8 µ), BEZ235 (5 µ), and tunicamycin + BEZ235 groups. Cell viability of each group was testified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Western blotting was applied to determine the expressions of endoplasmic reticulum stress and PI3K/AKT/mTOR pathwayrelated proteins and autophagy-and apoptosis-related proteins. Monodansylcadaverine and Annexin V-fluorescein isothiocyanate/propidium iodide staining were used for determination of cell autophagy and apoptosis. Furthermore, MCF-7 cells were divided into the control (without any treatment), tunicamycin (5 µM), cisplatin (16 µM), cisplatin (16 µM) + BEZ235 (5 µM), tunicamycin (5 µM) + cisplatin (16 µM), and tunicamycin (5 µM) + cisplatin (16 µM) + BEZ235 groups. Cell viability and apoptosis were also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining. In MCF-7 cells treated with tunicamycin, cell viability decreased significantly, but PEAK, eIF2, and CHOP were upregulated markedly and p-PI3K, p-AKT, and p-MTOR were downregulated in dose-and time-dependent manners. In the tunicamycin + BEZ235 group, the cell viability was lower and the apoptosis rate was higher than those of the control and monotherapy groups. Compared with the cisplatin group, the tunicamycin + cisplatin group showed a relatively higher growth inhibition rate; the growth inhibition rate substantially increased in the tunicamycin + cisplatin + BEZ235 group than the tunicamycin + cisplatin group. The apoptosis rate was highest in tunicamycin + cisplatin + BEZ235 group, followed by tunicamycin + cisplatin group and then cisplatin group. Our study provide evidence that endoplasmic reticulum stress activated by tunicamycin could promote breast cancer cell autophagy and apoptosis and enhance chemosensitivity of MCF-7 cells by inhibiting the PI3K/AKT/ mTOR signaling pathway.

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“…A recent publication using pathway network analyses revealed a major overlaps with various diseases and convergence upon MAPK and calcium signaling as well [11]. Studies using U0126, a selective MAPK kinase (MKK) inhibitor [12], have revealed a major effect on the deactivation of ERK1/2 [13] possibly even affecting MAPK-mediated mitochondrial-derived [14] and endoplasmic reticulum stress induced apoptosis [15]. …”

Section: Introductionmentioning

confidence: 99%

DecreasedTRPM7inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway

et al. 2016

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Transient receptor potential melastatin 7 (TRPM7) functions as a Mg2+/Ca2+-permeable channel fused with a kinase domain and regulates various physical processes and diseases. However, its effects on pathogenesis of human bladder cancer (BCa) has not been clarified yet. Our microarray analysis has suggested that calcium signaling pathway is connected with bladder cancer via MAPK pathway. Therefore, we aim to investigate the mechanism of TRPM7 in BCa tumorigenesis by using BCa tissues compared with normal bladder epithelium tissues, as well as using distinct BCa cell lines (EJ, 5637 and T24). We observed increased TRPM7 expression and dysregulation of proteins involved in Epithelial-Mesenchymal Transition (EMT) in BCa tissues. Moreover, knockdown of TRPM7 in BCa cells reversed the EMT status, accompanied by increase of reactive oxygen species (ROS). Furthermore, TRPM7 deficiency could inhibit BCa cell proliferation, migration and invasion, as well as induce p-ERK1/2 and suppress PI3K/AKT at the protein level. Downregulation of TRPM7 promoted cell cycle arrest at G0/G1 phase and apoptosis in vitro, which could be recovered by pre-treatment with U0126 to deactivate ERK1/2, suggesting a close correlation between TRPM7 and the MAPK signaling pathway. Furthermore, a NOD/SCID mouse model transplanted using the BCa cells was established, revealing delayed tumor growth by reduced protein activity and mRNA transcription of TRPM7 in vivo. Our results suggested TRPM7 might be essential for BCa tumorigenesis by interfering BCa cell proliferation, motility and apoptosis.

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Inhibition of mitogen-activated protein kinase signaling pathway sensitizes breast cancer cells to endoplasmic reticulum stress-induced apoptosis

Cited by 19 publications

References 29 publications

STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy

STAT3-induced lncRNA HAGLROS overexpression contributes to the malignant progression of gastric cancer cells via mTOR signal-mediated inhibition of autophagy

Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway

DecreasedTRPM7inhibits activities and induces apoptosis of bladder cancer cells via ERK1/2 pathway

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