Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Cui, Yan; Guo, Gang

doi:10.3390/ijms17111942

Cited by 100 publications

(75 citation statements)

References 138 publications

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“…Numerous lines of evidence indicate that tumor microenvironment could alter myeloid cells (macrophages, dendritic cells, and granulocytes) and make them become potent immunosuppressive cells. 68, 69 Tumor-associated macrophages contribute to tumor survival and invasion by secreting cytokines and chemokines, 70 as well as maintaining pro-tumor inflammation. 68, 69 Tumor associated dendritic cells have serious functional deficits and cause cancer immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

Zhao

Mao

et al. 2017

Mol. Pharmaceutics

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Advances in photodynamic therapy of cancer have been restrained by lack of cancer specificity and side effects to normal tissues. Molecularly targeted photodynamic therapy can achieve higher cancer specificity by combination of active cancer targeting and localized laser activation. We aimed to use albumin as a carrier to prepare targeted nanoconjugates that are selective to cancer cells and smaller than conventional nanoparticles for superior tumor penetration. IRDye® 700DX (IR700), a porphyrin photosensitizer, was covalently conjugated to human serum albumin that was also linked with tumor-targeting RGD peptides. With multiple IR700 and RGD molecules in a single albumin molecule, the resultant nanoconjugates demonstrated monodispersed and uniform size distribution with a diameter of 10.9 nm. These targeted nanoconjugates showed 121-fold increase in cellular delivery of IR700 into TOV21G ovarian cancer cells compared to control nanoconjugates. Mechanistic studies revealed that the integrin specific cellular delivery was achieved through dynamin-mediated caveolae-dependent endocytosis pathways. They produced massive cell killing in TOV21G cells at low nanomolar concentrations upon light irradiation, while NIH/3T3 cells that do not express integrin αvβ3 were not affected. Because of their small size, targeted albumin nanoconjugates could penetrate tumor spheroids of SKOV-3 ovarian cancer cells and produced strong phototoxicity in this 3-D model. Owing to their cancer-specific delivery and small size, these targeted nanoconjugates may become an effective drug delivery system for enabling molecularly targeted photodynamic therapy of cancer.

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Section: Discussionmentioning

confidence: 99%

RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

Zhao

Mao

et al. 2017

Mol. Pharmaceutics

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“…Intriguingly, miR-29b could upregulate the level of p53 [40], and consequently activate downstream the p53 pathway including caspases 3 and 8, which eventually induce the apoptosis of tumor cells [45]. In addition, the development of tumors often accompanies chronic inflammation and oxidant stress [46], and thus, the inflammatory cytokines and oxidant enzymes also play a significant role in tumor development. The normal activities of oxidant enzymes (MPO, MDA) could promote cell proliferation; however, the abnormal expression would upregulate the expression of p53 and miR-29b, inducing cell apoptosis [47].…”

Section: Discussionmentioning

confidence: 99%

“…The inflammatory cytokines also play a pivotal role in the procession and metastasis in the tumor, whereby the excess inflammatory factors would upregulate the miR-29b, p53, and caspases 3 and 8 levels to stimulate the tumor cell apoptosis [47,48,49]. Cui et al [46] demonstrated that the expression of p53 was upregulated in inflamed tissues, and then, p53 negatively regulated the pro-inflammatory factors. Moreover, the pro-inflammatory factors stimulated the expression of miR-29b and enhanced the anti-tumor effect mediated by enhancing the cell apoptosis [8].…”

Section: Discussionmentioning

confidence: 99%

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

Yang

Sun

Liang

et al. 2017

IJMS

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Bleomycin (BLM), a family of anti-tumor drugs, was reported to exhibit severe side effects limiting its usage in clinical treatment. Therefore, finding adjuvants that enhance the anti-tumor effect and reduce the detrimental effect of BLM is a prerequisite. Chrysanthemum indicum, an edible flower, possesses abundant bioactivities; the supercritical-carbon dioxide fluid extract from flowers and buds of C. indicum (CISCFE) have strong anti-inflammatory, anti-oxidant, and lung protective effects. However, the role of CISCFE combined with BLM treatment on tumor-bearing mice remains unclear. The present study aimed to investigate the potential synergistic effect and the underlying mechanism of CISCFE combined with BLM in the treatment of hepatoma 22 (H22) tumor-bearing mice. The results suggested that the oral administration of CISCFE combined with BLM could markedly prolong the life span, attenuate the BLM-induced pulmonary fibrosis, suppress the production of pro-inflammatory cytokines (interleukin-6), tumor necrosis factor-α, activities of myeloperoxidase, and malondiadehyde. Moreover, CISCFE combined with BLM promoted the ascites cell apoptosis, the activities of caspases 3 and 8, and up-regulated the protein expression of p53 and down-regulated the transforming growth factor-β1 by activating the gene expression of miR-29b. Taken together, these results indicated that CISCFE could enhance the anti-cancer activity of BLM and reduce the BLM-induced pulmonary injury in H22 tumor-bearing mice, rendering it as a potential adjuvant drug with chemotherapy after further investigation in the future.

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“…Tumor therapy strategies based on p53 activation are focused on tumor cell apoptosis and cell cycle arrest to protect from tumorigenesis or metastasis [20]. Recent compelling evidence indicates that p53 plays a crucial role in tumor suppression through regulating immune surveillance in the tumor microenvironment (TME) [21]. Meanwhile, elevated p53 is detected in contexts of chronic inflammation, autoimmune diseases and virus infections, including inflammatory bowel disease, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and HIV infection [22].…”

Section: Discussionmentioning

confidence: 99%

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

Zhang

Ren

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunosuppression frequently occurs during the development of sepsis and is closely associated with poor outcome. Characteristics of immunosuppressive CD4⁺ T lymphocytes in sepsis have been reported to include dramatic cell loss and inactivation. p53 acts as a pivotal transcription factor in regulating cell proliferation and apoptosis, which control tumorigenesis. However, few studies have investigated the universal role of p53 in immune cells, especially in the development of sepsis. Methods: A mouse model of sepsis was produced by cecal ligation and puncture (CLP), and isolated splenic CD4⁺ T cells or Jurkat cells were exposed to lipopolysaccharide (LPS) stimulation in vitro. We used genetic knockout (p53^-/-) mice or the specific inhibitor pifithrin-α (PFT) to investigate the regulatory mechanisms of p53. Cell proliferation ability was assessed using a Cell Counting Kit-8 assay, and apoptotic cells were stained with annexin V/propidium iodide and then analyzed using a FACScan flow cytometer. Protein and mRNA expression levels were measured by western blotting and real-time PCR, and cytokine levels in culture supernatants were determined by enzyme-linked immunosorbent assay. Results: Splenic CD4⁺ T lymphocytes from CLP mice expressed gradually elevated p53 mRNA and protein levels, which resulted in extracellular regulated protein kinase 1/2 inactivation and expression of apoptotic molecules. Specific inhibition of p53 by PFT or genetic knockout (p53^-/-) maintained CD4⁺ T lymphocyte homeostasis, as indicated by protection from cell loss and restoration of immune function. A medium dose of PFT improved the survival rate of mice, while mortality rate showed only a slight improvement in p53^-/- mice compared with wild-type mice. The in vitro responses to LPS were consistent with these results, and upregulation of p53 clearly affected the proliferation, apoptosis, and immune dysfunction of CD4⁺ T lymphocytes. In addition, we confirmed the regulatory effect of p53 in Jurkat cells, and inhibition of p53 by either inhibition or short hairpin RNA transduction markedly protected cells from LPS stimulation. Conclusion: Elevation of p53 in T lymphocytes during sepsis or endotoxin challenge might be responsible for inhibiting cell proliferation and enhancing both apoptosis and immune dysfunction of T cells.

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Immunomodulatory Function of the Tumor Suppressor p53 in Host Immune Response and the Tumor Microenvironment

Cited by 100 publications

References 138 publications

RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

RGD-Modified Albumin Nanoconjugates for Targeted Delivery of a Porphyrin Photosensitizer

Supercritical-Carbon Dioxide Fluid Extract from Chrysanthemum indicum Enhances Anti-Tumor Effect and Reduces Toxicity of Bleomycin in Tumor-Bearing Mice

Novel Role of p53 in Septic Immunosuppression: Involvement in Loss and Dysfunction of CD4+ T Lymphocytes

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