Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

Sípos, Ferenc; Barta, Bettina Bohusné; Simon, Ágnes; Nagy, Lőrinc; Dankó, Titanilla; Raffay, Regina; Petővári, Gábor; Zsiros, Viktória; Wichmann, Barnabás; Sebestyén, Anna; Műzes, Györgyi

doi:10.3389/pore.2022.1610322

Cited by 6 publications

(8 citation statements)

References 68 publications

(79 reference statements)

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“…Autophagy is often compared to a double-edged sword in CRC therapy, as it can both lead to the death of cancer cells and promote their survival [ 27 , 32 ]. Regulatory mechanisms and inducing factors of autophagy, including small-molecule compounds (e.g., miRNAs, natural products, chemicals and radiation) in CRC cells are already presented in other papers [ 25 , 238 , 239 ].…”

Section: Autophagy and Igf System: Implications For Therapy In Crcmentioning

confidence: 99%

“…Potential CRC treatment strategies using knowledge of autophagy and IGF-1R signaling interactions are increasingly emerging [ 26 , 27 , 191 , 202 , 242 , 243 , 244 ]. In an in vitro model (HCT116 cells), it has been demonstrated that the use of branched chain AA (BCAA) supplementation significantly reduced insulin-initiated CRC cell proliferation.…”

Section: Autophagy and Igf System: Implications For Therapy In Crcmentioning

confidence: 99%

“…The different effects of IGF-1R (picropodophyllin), TLR9 (ODN2088) and autophagy (chloroquine) inhibitors (per se or in combination) on HT29 cells suggested that the IGF-1R-related or non-IGF-1R-related autophagy process, however, also had “Janus-faced” characteristics in terms of its effect on CRC cell proliferation. The autophagy process induced by different combinations of self-DNA and inhibitors did not prevent HT-29 cell death but yielded the survival of some CD133+ HT-29 cells with stem-like cell features and can be the cause of CRC recurrence [ 27 ].…”

Section: Autophagy and Igf System: Implications For Therapy In Crcmentioning

confidence: 99%

“…The role of IGF signaling in the autophagy process in CRC is only partially understood [ 26 , 27 ]. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia

Kasprzak

2023

IJMS

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Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Along with apoptosis and inflammation, autophagy is one of three important mechanisms in CRC. The presence of autophagy/mitophagy in most normal mature intestinal epithelial cells has been confirmed, where it has mainly protective functions against reactive oxygen species (ROS)-induced DNA and protein damage. Autophagy regulates cell proliferation, metabolism, differentiation, secretion of mucins and/or anti-microbial peptides. Abnormal autophagy in intestinal epithelial cells leads to dysbiosis, a decline in local immunity and a decrease in cell secretory function. The insulin-like growth factor (IGF) signaling pathway plays an important role in colorectal carcinogenesis. This is evidenced by the biological activities of IGFs (IGF-1 and IGF-2), IGF-1 receptor type 1 (IGF-1R) and IGF-binding proteins (IGF BPs), which have been reported to regulate cell survival, proliferation, differentiation and apoptosis. Defects in autophagy are found in patients with metabolic syndrome (MetS), inflammatory bowel diseases (IBD) and CRC. In neoplastic cells, the IGF system modulates the autophagy process bidirectionally. In the current era of improving CRC therapies, it seems important to investigate the exact mechanisms not only of apoptosis, but also of autophagy in different populations of tumor microenvironment (TME) cells. The role of the IGF system in autophagy in normal as well as transformed colorectal cells still seems poorly understood. Hence, the aim of the review was to summarize the latest knowledge on the role of the IGF system in the molecular mechanisms of autophagy in the normal colon mucosa and in CRC, taking into account the cellular heterogeneity of the colonic and rectal epithelium.

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Section: Autophagy and Igf System: Implications For Therapy In Crcmentioning

confidence: 99%

Section: Autophagy and Igf System: Implications For Therapy In Crcmentioning

confidence: 99%

Section: Autophagy and Igf System: Implications For Therapy In Crcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia

Kasprzak

2023

IJMS

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“…In another study [ 241 ], we discovered that the tumorous self-DNA and insulin-like growth factor 1 receptor (IGF1R) inhibition display anti-proliferative properties that can be suppressed by inhibiting the TLR9 signaling. The different effects of the IGF1R, TLR9, and autophagy inhibitors on the HT29 cell proliferation and autophagy suggest that the IGF1R-associated and non-IGF1R-associated autophagy machinery are “Janus-faced” regarding cell proliferation.…”

Section: Modification Of Cell-free Dna To Influence the Tumor Cell Ph...mentioning

confidence: 99%

Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors

Műzes¹,

Barta²,

Szabó³

et al. 2022

Biomedicines

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The basic function of the immune system is the protection of the host against infections, along with the preservation of the individual antigenic identity. The process of self-tolerance covers the discrimination between self and foreign antigens, including proteins, nucleic acids, and larger molecules. Consequently, a broken immunological self-tolerance results in the development of autoimmune or autoinflammatory disorders. Immunocompetent cells express pattern-recognition receptors on their cell membrane and cytoplasm. The majority of endogenous DNA is located intracellularly within nuclei and mitochondria. However, extracellular, cell-free DNA (cfDNA) can also be detected in a variety of diseases, such as autoimmune disorders and malignancies, which has sparked interest in using cfDNA as a possible biomarker. In recent years, the widespread use of liquid biopsies and the increasing demand for screening, as well as monitoring disease activity and therapy response, have enabled the revival of cfDNA research. The majority of studies have mainly focused on the function of cfDNA as a biomarker. However, research regarding the immunological consequences of cfDNA, such as its potential immunomodulatory or therapeutic benefits, is still in its infancy. This article discusses the involvement of various DNA-sensing receptors (e.g., absent in melanoma-2; Toll-like receptor 9; cyclic GMP–AMP synthase/activator of interferon genes) in identifying host cfDNA as a potent danger-associated molecular pattern. Furthermore, we aim to summarize the results of the experimental studies that we recently performed and highlight the immunomodulatory capacity of cfDNA, and thus, the potential for possible therapeutic consideration.

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Notch1 hyperactivity drives ubiquitination of NOX2 and dysfunction of CD8+ regulatory T cells in patients with systemic lupus erythematosus

Yuan,

Liu,

Zhang

et al. 2024

Rheumatology

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Objectives Patients with systemic lupus erythematosus (SLE) display heightened immune activation and elevated IgG autoantibody levels, indicating compromised regulatory T cell (Tregs) function. Our recent findings pinpoint CD8+ Tregs as crucial regulators within secondary lymphoid organs, operating in a NOX2-dependent mechanism. However, the specific involvement of CD8+ Tregs in SLE pathogenesis and the mechanisms underlying their role remain uncertain. Methods SLE and healthy individuals were enlisted to assess the quantity and efficacy of Tregs. CD8+CD45RA+CCR7+ Tregs were generated ex vivo, and their suppressive capability was gauged by measuring pZAP70 levels in targeted T cells. Notch1 activity was evaluated by examining activated Notch1 and HES1, with manipulation of Notch1 accomplished with Notch inhibitor DAPT, Notch1 shRNA, and Notch1-ICD. To create humanized SLE chimeras, immune-deficient NSG mice were engrafted with PBMCs from SLE patients. Results We observed a reduced frequency and impaired functionality of CD8+ Tregs in SLE patients. There was a downregulation of NOX2 in CD8+ Tregs from SLE patients, leading to a dysfunction. Mechanistically, the reduction of NOX2 in SLE CD8+ Tregs occurred at a post-translational level rather than at the transcriptional level. SLE CD8+ Tregs exhibited heightened Notch1 activity, resulting in increased expression of STUB1, an E3 ubiquitin ligase that binds to NOX2 and facilitates its ubiquitination. Consequently, restoring NOX2 levels and inhibiting Notch1 activity could alleviate the severity of the disease in humanized SLE chimeras. Conclusion Notch1 is the cell-intrinsic mechanism underlying NOX2 deficiency and CD8+ Treg dysfunction, serving as a therapeutic target for clinical management of SLE.

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Survival of HT29 Cancer Cells Is Affected by IGF1R Inhibition via Modulation of Self-DNA-Triggered TLR9 Signaling and the Autophagy Response

Cited by 6 publications

References 68 publications

Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia

Autophagy and the Insulin-like Growth Factor (IGF) System in Colonic Cells: Implications for Colorectal Neoplasia

Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors

Notch1 hyperactivity drives ubiquitination of NOX2 and dysfunction of CD8+ regulatory T cells in patients with systemic lupus erythematosus

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