PTEN/AKT signaling pathway related to hTERT downregulation and telomere shortening induced in Toxoplasma GRA16-expressing colorectal cancer cells

Seo, Seunghwan; Shin, Ji-Hun; Ham, Do-Won; Shin, Eun‐Hee

doi:10.1016/j.biopha.2022.113366

Cited by 3 publications

(4 citation statements)

References 26 publications

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“…48 PTEN is a classical tumor suppressor that regulates important cell functions, including cell proliferation, differentiation, and metastasis. [49][50][51] Most anticancer effects of PTEN depend on its lipid phosphatase activity. PI3K/AKT signaling is one of the best-characterized pathways negatively targeted by PTEN through its phosphatase activity.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a previous study has reported that FGFR1 downregulates PTEN protein expression in stem cell leukemia/lymphoma syndrome 48 . PTEN is a classical tumor suppressor that regulates important cell functions, including cell proliferation, differentiation, and metastasis 49–51 . Most anticancer effects of PTEN depend on its lipid phosphatase activity.…”

Section: Discussionmentioning

confidence: 99%

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MiR‐2110 induced by chemically synthesized cinobufagin functions as a tumor‐metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma

Fang,

Peng,

Zhang

et al. 2024

Environmental Toxicology

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Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma (NPC). MiR‐2110 was cloned and identified in Epstein–Barr virus (EBV)‐positive NPC, but its role is unclear in NPC. In this study, we investigated the effect of miR‐2110 on NPC metastasis and its related molecular basis. In addition, we also explored whether miR‐2110 can be regulated by cinobufotalin (CB) and participate in the inhibition of CB on NPC metastasis. Bioinformatics, RT‐PCR, and in situ hybridization were used to observe the expression of miR‐2110 in NPC tissues and cells. Scratch, Boyden, and tail vein metastasis model of nude mouse were used to detect the effect of miR‐2110 on NPC metastasis. Western blot, Co‐IP, luciferase activity, colocalization of micro confocal and ubiquitination assays were used to identify the molecular mechanism of miR‐2110 affecting NPC metastasis. Finally, miR‐2110 induced by CB participates in CB‐stimulated inhibition of NPC metastasis was explored. The data showed that increased miR‐2110 significantly suppresses NPC cell migration, invasion, and metastasis. Suppressing miR‐2110 markedly restored NPC cell migration and invasion. Mechanistically, miR‐2110 directly targeted FGFR1 and reduced its protein expression. Decreased FGFR1 attenuated its recruitment of NEDD4, which downregulated NEDD4‐induced phosphatase and tensin homolog (PTEN) ubiquitination and degradation and further increased PTEN protein stability, thereby inactivating PI3K/AKT‐stimulated epithelial–mesenchymal transition signaling and ultimately suppressing NPC metastasis. Interestingly, CB, a potential new inhibitory drug for NPC metastasis, significantly induced miR‐2110 expression by suppressing PI3K/AKT/c‐Jun‐mediated transcription inhibition. Suppression of miR‐2110 significantly restored cell migration and invasion in CB‐treated NPC cells. Finally, a clinical sample assay indicated that reduced miR‐2110 was negatively correlated with NPC lymph node metastasis and positively related to NPC patient survival prognosis. In summary, miR‐2110 is a metastatic suppressor involving in CB‐induced suppression of NPC metastasis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MiR‐2110 induced by chemically synthesized cinobufagin functions as a tumor‐metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma

Fang,

Peng,

Zhang

et al. 2024

Environmental Toxicology

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“…GRA16 has been found to up-regulate the expression of protein phosphatase 2A regulatory subunit (B55PP2A-B55) and inhibit the phosphorylation of AKT, leading to NF-κB inactivation and the reversal of drug resistance in cancer cells ( Seo et al., 2020 ). Subsequent research by the same group has shown that after transgenic expression of GRA16 in colorectal cancer cell line HCT116, it can promote the activation of tumor suppressor phosphatase and tensin homolog (PTEN), leading to telomerase inactivation and achieving the effect of promoting tumor cell apoptosis in vitro ( Seo et al., 2022 ). Additionally, GRA8 can promote the efficacy of tumor-targeted drugs by interacting with mitochondrial protein ATP synthase F1 subunit alpha/sirtuin-3 both in vitro and in vivo ( Kim et al., 2020 ).…”

Section: T Gondiimentioning

confidence: 99%

A novel enemy of cancer: recent investigations into protozoan anti-tumor properties

Zheng,

Lu,

Zhou

et al. 2024

Front. Cell. Infect. Microbiol.

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Cancer remains a significant global health issue, despite advances in screening and treatment. While existing tumor treatment protocols such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy have proven effective in enhancing the prognosis for some patients, these treatments do not benefit all patients. Consequently, certain types of cancer continue to exhibit a relatively low 5-year survival rate. Therefore, the pursuit of novel tumor intervention strategies may help improve the current effectiveness of tumor treatment. Over the past few decades, numerous species of protozoa and their components have exhibited anti-tumor potential via immune and non-immune mechanisms. This discovery introduces a new research direction for the development of new and effective cancer treatments. Through in vitro experiments and studies involving tumor-bearing mice, the anti-tumor ability of Toxoplasma gondii, Plasmodium, Trypanosoma cruzi, and other protozoa have unveiled diverse mechanisms by which protozoa combat cancer, demonstrating encouraging prospects for their application. In this review, we summarize the anti-tumor ability and anti-tumor mechanisms of various protozoa and explore the potential for their clinical development and application.

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“…Toxoplasma gondii is an obligate intracellular protozoan that can invade and replicate in various warm-blooded animals cells [1,2]. After cell invasion by T. gondii, dense granules discharge secretory proteins that regulate parasitophorous vacuole formation, host cell pathogenicity, and immunity for survival [3,4]. Among them, GRA16, GRA24, and an inhibitor of STAT1 transcription (IST) invade the host nucleus and regulate host signaling pathways [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes

Seo,

Lee,

Ham

et al. 2024

Parasites Hosts Dis

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The dense granule protein of Toxoplasma gondii, inhibitor of signal transducer and activator of transcription 1 (IST) is an inhibitor of signal transducer and activator of transcription 1 (STAT1) transcriptional activity that binds to STAT1 and regulates the expression of inflammatory molecules in host cells. A sterile inflammatory liver injury in pathological acute liver failures occurs when excessive innate immune function, such as the massive release of IFN-γ and TNF-α, is activated without infection. In relation to inflammatory liver injury, we hypothesized that Toxoplasma gondii inhibitor of STAT1 transcription (TgIST) can inhibit the inflammatory response induced by activating the STAT1/IRF-1 mechanism in liver inflammation. This study used IFN-γ and TNF-α as inflammatory inducers at the cellular level of murine hepatocytes (Hepa-1c1c7) to determine whether TgIST inhibits the STAT1/IRF-1 axis. In stable cells transfected with TgIST, STAT1 expression decreased with a decrease in interferon regulatory factor (IRF)-1 levels. Furthermore, STAT1 inhibition of TgIST resulted in lower levels of NF-κB and COX2, as well as significantly lower levels of class II transactivator (CIITA), iNOS, and chemokines (CLXCL9/10/11). TgIST also significantly reduced the expression of hepatocyte proapoptotic markers (Caspase3/8/9, P53, and BAX), which are linked to sterile inflammatory liver injury. TgIST also reduced the expression of adhesion (ICAM-1 and VCAM-1) and infiltration markers of programmed death-ligand 1 (PD-L1) induced by hepatocyte and tissue damage. TgIST restored the cell apoptosis induced by IFN-γ/TNF-α stimulation. These results suggest that TgIST can inhibit STAT1-mediated inflammatory and apoptotic responses in hepatocytes stimulated with proinflammatory cytokines.

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PTEN/AKT signaling pathway related to hTERT downregulation and telomere shortening induced in Toxoplasma GRA16-expressing colorectal cancer cells

Cited by 3 publications

References 26 publications

MiR‐2110 induced by chemically synthesized cinobufagin functions as a tumor‐metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma

MiR‐2110 induced by chemically synthesized cinobufagin functions as a tumor‐metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma

A novel enemy of cancer: recent investigations into protozoan anti-tumor properties

Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes

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