PRKAA1 Promotes Proliferation and Inhibits Apoptosis of Gastric Cancer Cells Through Activating JNK1 and Akt Pathways

Zhang, Yangmei; Zhou, Xichang; Cheng, Long; Wang, Xiang; Zhang, Youwei; Sun, Shuai

doi:10.3727/096504019x15668125347026

Cited by 18 publications

(15 citation statements)

References 42 publications

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“…Conversely, the overexpression of PCSK9 in MGC-803 cells facilitated MAPK signaling pathway, accelerating the migration/invasion of the cells when compared with the controls. Previous studies have shown that MAPK signaling pathway plays a central role in the stimulation of cancer cell proliferation, apoptosis, and metastasis (35)(36)(37). And also p38 MAPK participates in resistance to chemotherapy drugs like cisplatin, irinotecan, and 5-fluorouracil (38), which are often administered in GC chemotherapy regimens.…”

Section: Discussionmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Fang

et al. 2021

Front. Oncol.

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ObjectiveTo examine the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) on gastric cancer (GC) progression and prognosis, and to explore the underlying mechanism.MethodsPCSK9 expression levels in human GC tissues were determined by quantitative real-time PCR, western blotting, and immunohistochemical assay. PCSK9 serum levels were detected by enzyme-linked immunosorbent assay. The relationships of PCSK9 and GC progression and survival were analyzed using the Chi-square test, Kaplan-Meier analysis, and Cox proportional hazards model. The effect of PCSK9 on cell invasion, migration, and apoptosis were determined in human GC cell lines and mouse xenograft model separately using PCSK9 knockdown and overexpression strategies. The PCSK9 interacting molecules, screened by co-immunoprecipitation combined with LC-MS/MS, were identified by immunofluorescence localization and western blotting. Additionally, the mitogen-activated protein kinase (MAPK) pathway was assessed by western blotting.ResultsPCSK9 mRNA and protein levels were significantly elevated in GC tissues compared with the paired normal tissues at our medical center (P < 0.001). Notably, the up-regulation of PCSK9 expression in GC tissues was related to tumor progression and poor survival. GC patients had higher serum levels of PCSK9 than the age-matched healthy controls (P < 0.001); PCSK9 promoted invasive and migratory ability and inhibited apoptosis in GC cells with no apparent affection in cell proliferation. The silencing of PCSK9 reversed these effects, suppressing tumor metastasis in vitro and in vivo. Furthermore, PCSK9 maintained these functions through up-regulating heat shock protein 70 (HSP70), ultimately facilitating the mitogen-activated protein kinase (MAPK) pathway.ConclusionCollectively, our data revealed that high PCSK9 expression levels in GC tissue were correlated with GC progression and poor prognosis and that PCSK9 could promote GC metastasis and suppress apoptosis by facilitating MAPK signaling pathway through HSP70 up-regulation. PCSK9 may represent a novel potential therapeutic target in GC.

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Section: Discussionmentioning

confidence: 99%

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Fang

et al. 2021

Front. Oncol.

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“…Genetic alteration, expression, and activity of AKT1, MAPK1, and MAPK3 can also affect the risk of developing GC, clinical outcomes, recurrence, and survival rates in patients [67][68][69] . Additionally, c-Jun NH2-terminal kinase 1 (JNK1; encoded by MAPK8), a kinase that coordinates cell migration, apoptosis, survival, and proliferation, plays an important role in the carcinogenesis and development of GC [70][71][72][73] . Furthermore, genetic mutations in PI3KCA is a determinant of the chemosensitivity of GC 74 .…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Perspective Investigation of the Pharmacological Mechanisms of the Herbal Drug FDY003 in Gastric Cancer

Lee¹,

Kang

Park³

et al. 2022

Natural Product Communications

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Gastric cancer (GC) is one of the most common and deadly malignant tumors worldwide. While the application of herbal drugs for GC treatment is increasing, the multicompound–multitarget pharmacological mechanisms involved are yet to be elucidated. By adopting a network pharmacology strategy, we investigated the properties of the anticancer herbal drug FDY003 against GC. We found that FDY003 reduced the viability of human GC cells and enhanced their chemosensitivity. We also identified 8 active phytochemical compounds in FDY003 that target 70 GC-associated genes and proteins. Gene ontology (GO) enrichment analysis suggested that the targets of FDY003 are involved in various cellular processes, such as cellular proliferation, survival, and death. We further identified various major FDY003 target GC-associated pathways, including PIK3-Akt, MAPK, Ras, HIF-1, ErbB, and p53 pathways. Taken together, the overall analysis presents insight at the systems level into the pharmacological activity of FDY003 against GC.

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“…As a cell energy sensor, it regulates intracellular nutrition and energy levels via glucose and lipid metabolic pathways [57]. Studies have recently reported that PRKAA1 modulates GC cell proliferation via the regulation of the c-JNK, AKT, and NF-κB signaling pathways [58,59]. Protein-protein interactions are the cornerstone of numerous biological functions.…”

Section: Discussionmentioning

confidence: 99%

MTFR2, A Potential Biomarker for Prognosis and Immune Infiltrates, Promotes Progression of Gastric Cancer Based on Bioinformatics Analysis and Experiments

Zhu¹,

Wang²,

Zhu³

et al. 2021

J. Cancer

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Background: Mitochondrial fission regulator 2 (MTFR2) which can promote mitochondrial fission, has recently been reported to be involved in tumorigenesis. However, little is known about its expression levels and function in gastric cancer (GC). This study aims to clarify the role of MTFR2 in GC. Methods:We firstly determined the expression level and prognostic value of MTFR2 in GC by integrated bioinformatics (Oncomine, GEPIA, Kaplan-Meier Plotter database) and experimental approaches (RT-qPCR, western blot, immunohistochemistry). After constructing stable down-regulated GC cells, the biological functions of MTFR2 in vitro and in vivo were studied through cell clone formation, wound healing, transwell and tumor formation experiments.To understand the reason for the high expression of MTFR2 in GC, copy number alternation, promoter methylation and mutation of MTFR2 were detected by UALCAN and cBioPortal. TargetScanHuman and PROMO databases were also used to explore the miRNAs and transcription factors of MTFR2, and the regulatory network was visualized by Cytoscape. LinkedOmics was used to detect the co-expression profile, and then these co-expressed genes were used for gene oncology function and pathway enrichment analysis to deepen the understanding of MTFR2 mechanism. The protein interaction network of MTFR2 was constructed by the GeneMANIA platform. Docking study of the binding mode was conducted by H DOCK webserver, and PYMOL is used for visualization, and analysis. TIMER database was used to explore the correlation between MTFR2 expression level and immune cells infiltration and gene markers of tumor infiltrating immune cells. Results: We demonstrated that MTFR2 was up-regulated in GC, and its overexpression led to poorer prognosis. MTFR2 downregulation inhibited the proliferation, migration, and invasion of GC cells in vitro and in vivo. By bioinformatics analysis, we identified the possible factors in MTFR2 overexpression. Moreover, function and pathway enrichment analyses found that MTFR2 was involved in chromosome segregation, catalytic activity, cell cycle, and ribonucleic acid transport. A MTFR2-protein interaction network revealed a potential direct protein interaction between MTFR2 and protein kinase adenosine-monophosphate-activated catalytic subunit alpha 1 (PRKAA1), and their potential binding site was predicted in a molecular docking model. In addition, we also found that MTFR2 may be correlated with immune infiltration in GC. Conclusions: Our study has effectively revealed the expression, prognostic value, potential functional networks, protein interactions and immune infiltration of MTFR2 in GC. Altogether, our data identify the possible underlying mechanisms of MTFR2 and suggest that MTFR2 may be a prognostic biomarker and therapeutic target in GC.

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PRKAA1 Promotes Proliferation and Inhibits Apoptosis of Gastric Cancer Cells Through Activating JNK1 and Akt Pathways

Cited by 18 publications

References 42 publications

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

Proprotein Convertase Subtilisin/Kexin Type 9 Promotes Gastric Cancer Metastasis and Suppresses Apoptosis by Facilitating MAPK Signaling Pathway Through HSP70 Up-Regulation

A Network Pharmacology Perspective Investigation of the Pharmacological Mechanisms of the Herbal Drug FDY003 in Gastric Cancer

MTFR2, A Potential Biomarker for Prognosis and Immune Infiltrates, Promotes Progression of Gastric Cancer Based on Bioinformatics Analysis and Experiments

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