Cancer/testis antigen LDHC promotes proliferation and metastasis by activating the PI3K/Akt/GSK-3β-signaling pathway and the in lung adenocarcinoma

Chen, Liangyuan; Wu, Qiumei; Xu, Xunyu; Yang, Cheng-Ao; You, Jianbin; Chen, Falin; Zeng, Yanfen

doi:10.1016/j.yexcr.2020.112414

Cited by 29 publications

(23 citation statements)

References 27 publications

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“…AKT could phosphorylate and inactivate GSK-3b at Ser9 (48,49), which subsequently stabilized Snail protein and finally caused EMT (50,51). Consistently, accumulated evidence revealed that activation of PI3K/AKT/GSK-3b pathway resulted in lung cancer progression (52), hepatocellular carcinoma metastasis (53) and so on. These data suggested that Agrin might exert its prooncogenic function via PI3K/AKT pathway, with GSK-3b as a potential downstream target.…”

Section: Discussionmentioning

confidence: 77%

Agrin Promotes Non-Small Cell Lung Cancer Progression and Stimulates Regulatory T Cells via Increasing IL-6 Secretion Through PI3K/AKT Pathway

Shi

Luo

et al. 2022

Front. Oncol.

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Non-small cell lung cancer (NSCLC) has high mortality rates worldwide. Agrin contributes to immune synapse information and is involved in tumor metastasis. However, its roles in NSCLC and tumor immune microenvironment remain unclear. This study examined the effects and the underlying mechanisms of Agrin in NSCLC and tumor-infiltrated immune cells. Clinical tissue samples were used to confirm the bioinformatic predictions. NSCLC cells were used to investigate the effects of Agrin on cell cycle and proliferation, as well as invasion and migration. Tumor xenograft mouse model was used to confirm the effects of Agrin on NSCLC growth and tumor-infiltrated regulatory T cells (Tregs) in vivo. Agrin levels in NSCLC cells were closely related to tumor progression and metastasis, and its function was enriched in the PI3K/AKT pathway. In vitro assays demonstrated that Agrin knockdown suppressed NSCLC cell proliferation and metastasis, while PI3K/AKT activators reversed the inhibitory effects of Agrin deficiency on NSCLC cell behaviors. Agrin expression was negatively associated with immunotherapy responses in NSCLC patients. Agrin knockdown suppressed Tregs, as well as interleukin (IL)-6 expression and secretion, while PI3K/AKT activators and exogenous IL-6 rescued the inhibitory effects. In the mouse model, Agrin downregulation alleviated NSCLC cell growth and Treg infiltration in vivo. Our results indicated that Agrin promotes tumor cell growth and Treg infiltration via increasing IL-6 expression and secretion through PI3K/AKT pathway in NSCLC. Our studies suggested Agrin as a therapeutically potential target to increase the efficacy of immunotherapy in NSCLC patients.

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Section: Discussionmentioning

confidence: 77%

Agrin Promotes Non-Small Cell Lung Cancer Progression and Stimulates Regulatory T Cells via Increasing IL-6 Secretion Through PI3K/AKT Pathway

Shi

Luo

et al. 2022

Front. Oncol.

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“…The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is hyperactivated or altered in many cancer types (26)(27)(28) and regulates a broad range of cellular processes (29,30). It is well known that Akt can phosphorylate and inhibit GSK-3b activity, subsequently suppressing the GSK-3b-mediated phosphorylation of Snail1 and facilitating its stabilization and nuclear localization, which ultimately promotes EMT widely presenting in a variety of tumors (31)(32)(33)(34)(35)(36). In addition to GSK-3b, PI3K-Akt also activates mTOR, thereby potentiating Snail1 expression in gastric, breast, pancreatic and ovarian cancer (37)(38)(39)(40).…”

Section: Pi3k-akt Pathwaymentioning

confidence: 99%

SNAIL1: Linking Tumor Metastasis to Immune Evasion

et al. 2021

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The transcription factor Snail1, a key inducer of epithelial-mesenchymal transition (EMT), plays a critical role in tumor metastasis. Its stability is strictly controlled by multiple intracellular signal transduction pathways and the ubiquitin-proteasome system (UPS). Increasing evidence indicates that methylation and acetylation of Snail1 also affects tumor metastasis. More importantly, Snail1 is involved in tumor immunosuppression by inducing chemokines and immunosuppressive cells into the tumor microenvironment (TME). In addition, some immune checkpoints potentiate Snail1 expression, such as programmed death ligand 1 (PD-L1) and T cell immunoglobulin 3 (TIM-3). This mini review highlights the pathways and molecules involved in maintenance of Snail1 level and the significance of Snail1 in tumor immune evasion. Due to the crucial role of EMT in tumor metastasis and tumor immunosuppression, comprehensive understanding of Snail1 function may contribute to the development of novel therapeutics for cancer.

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“…LDH-C was found to be predominantly expressed in the growing testes and spermatozoa ( Rodriguez et al, 2003 ), with no clear relation to cancer pathogenesis. Some reports demonstrated enhanced LDH-C expression in various tumours such as lung, melanoma, kidney, and breast ( Koslowski et al, 2002 ; Kong et al, 2016 ; Hua et al, 2017 ; Chen et al, 2021 ), and being a promising target for cancer therapy ( Thomas et al, 2020 ; Naik and Decock, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro

2021

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Background: Lactate dehydrogenase (LDH) plays an important role in cancer pathogenesis and enhanced expression/activity of this enzyme has been correlated with poor prognosis. In this study we determined the expression profile of LDH-A and B in normal as well as in endocrine-resistant and -responsive breast cancer cells and the effect of their knockdown on LDH activity, lactate production, proliferation and cell motility.Methods: Knockdown experiments were performed using siRNA and shRNA. The expression profile of LDH and signaling molecules was determined using PCR and western blotting. Intracellular LDH activity and extracellular lactate levels were measured by a biochemical assay. Cell motility was determined using wound healing, while proliferation was determined using MTT assay.Results: LDH-A was expressed in all of the tested cell lines, while LDH-B was specifically expressed only in normal and endocrine-resistant breast cancer cells. This was correlated with significantly enhanced LDH activity and lactate production in endocrine resistant breast cancer cells when compared to normal or endocrine responsive cancer cells. LDH-A or -B knockdown significantly reduced LDH activity and lactate production, which led to reduced cell motility. Exogenous lactate supplementation enhanced cell motility co-incident with enhanced phosphorylation of ERK1/2 and reduced E-cadherin expression. Also, LDH-A or -B knockdown reduced ERK 1/2 phosphorylation.Conclusion: Enhanced cell motility in endocrine resistant breast cancer cells is at least in part mediated by enhanced extracellular lactate levels, and LDH inhibition might be a promising therapeutic target to inhibit cancer cell motility.

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Cancer/testis antigen LDHC promotes proliferation and metastasis by activating the PI3K/Akt/GSK-3β-signaling pathway and the in lung adenocarcinoma

Cited by 29 publications

References 27 publications

Agrin Promotes Non-Small Cell Lung Cancer Progression and Stimulates Regulatory T Cells via Increasing IL-6 Secretion Through PI3K/AKT Pathway

Agrin Promotes Non-Small Cell Lung Cancer Progression and Stimulates Regulatory T Cells via Increasing IL-6 Secretion Through PI3K/AKT Pathway

SNAIL1: Linking Tumor Metastasis to Immune Evasion

Lactate Dehydrogenase A or B Knockdown Reduces Lactate Production and Inhibits Breast Cancer Cell Motility in vitro

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