Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape

Sakhnevych, Svetlana; Yasinska, Inna M.; Fasler‐Kan, Elizaveta; Sumbayev, Vadim V.

doi:10.3389/fphar.2019.00342

Cited by 10 publications

(10 citation statements)

References 10 publications

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“…On cell assays were employed to detect surface presence of galectin-9 and CD8. We used Li-Cor secondary antibody to recognize anti CD8 primary antibody and then visualized as described before (4, 17).…”

Section: Methodsmentioning

confidence: 99%

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

et al. 2019

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Human cancer cells operate a variety of effective molecular and signaling mechanisms which allow them to escape host immune surveillance and thus progress the disease. We have recently reported that the immune receptor Tim-3 and its natural ligand galectin-9 are involved in the immune escape of human acute myeloid leukemia (AML) cells. These cells use the neuronal receptor latrophilin 1 (LPHN1) and its ligand fibronectin leucine rich transmembrane protein 3 (FLRT3, and possibly other ligands) to trigger the pathway. We hypothesized that the Tim-3-galectin-9 pathway may be involved in the immune escape of cancer cells of different origins. We found that studied breast tumors expressed significantly higher levels of both galectin-9 and Tim-3 compared to healthy breast tissues of the same patients and that these proteins were co-localized. Increased levels of LPHN2 and expressions of LPHN3 as well as FLRT3 were also detected in breast tumor cells. Activation of this pathway facilitated the translocation of galectin-9 onto the tumor cell surface, however no secretion of galectin-9 by tumor cells was observed. Surface-based galectin-9 was able to protect breast carcinoma cells against cytotoxic T cell-induced death. Furthermore, we found that cell lines from brain, colorectal, kidney, blood/mast cell, liver, prostate, lung, and skin cancers expressed detectable amounts of both Tim-3 and galectin-9 proteins. The majority of cell lines expressed one of the LPHN isoforms and FLRT3. We conclude that the Tim-3-galectin-9 pathway is operated by a wide range of human cancer cells and is possibly involved in prevention of anti-tumor immunity.

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Section: Methodsmentioning

confidence: 99%

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

et al. 2019

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“…We then tested if naturally occurring, dying cell-derived HMGB1 can induce similar effects in TLR4 expressing cells. We exposed several types of human cancer cell lines (THP-1, Colo 205 and MCF-7) for 24 h to 100 µM BH3I-1 (5-[(4-bromophenyl)methylene]-a-(1-methylethyl)-4-oxo-2-thioxo-3-thiazolidineacetic acid), which is a synthetic cell-permeable Bcl-XL antagonist that induces apoptosis (by inhibiting the interactions between the BH3 domain and Bcl-XL thus defunctionalising mitochondria) ( 23 ). We found that upon stimulation with BH3I-1 THP-1 released the highest amounts of HMGB1 ( Supplementary Figure 7 ).…”

Section: Resultsmentioning

confidence: 99%

High Mobility Group Box 1 (HMGB1) Induces Toll-Like Receptor 4-Mediated Production of the Immunosuppressive Protein Galectin-9 in Human Cancer Cells

et al. 2021

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High mobility group box 1 (HMGB1) is a non-histone protein which is predominantly localised in the cell nucleus. However, stressed, dying, injured or dead cells can release this protein into the extracellular matrix passively. In addition, HMGB1 release was observed in cancer and immune cells where this process can be triggered by various endogenous as well as exogenous stimuli. Importantly, released HMGB1 acts as a so-called “danger signal” and could impact on the ability of cancer cells to escape host immune surveillance. However, the molecular mechanisms underlying the functional role of HMGB1 in determining the capability of human cancer cells to evade immune attack remain unclear. Here we report that the involvement of HMGB1 in anti-cancer immune evasion is determined by Toll-like receptor (TLR) 4, which recognises HMGB1 as a ligand. We found that HGMB1 induces TLR4-mediated production of transforming growth factor beta type 1 (TGF-β), displaying autocrine/paracrine activities. TGF-β induces production of the immunosuppressive protein galectin-9 in cancer cells. In TLR4-positive cancer cells, HMGB1 triggers the formation of an autocrine loop which induces galectin-9 expression. In malignant cells lacking TLR4, the same effect could be triggered by HMGB1 indirectly through TLR4-expressing myeloid cells present in the tumour microenvironment (e. g. tumour-associated macrophages).

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“…In agreement with other reports, Chiyo and coworkers demonstrated that Gal-9 induces apoptosis in esophageal squamous cell carcinoma through the mitochondria [ 85 ]. Sakhnevych et al found that Gal-9 and its receptor Tim-3 form a complex and accumulate in the mitochondria in response to a Bcl-X L antagonist in colorectal cancer cells [ 84 ]. Extracellular Gal-7 can reenter cells and translocate into the nucleus to interact with bcl-2 as an anti-apoptosis function to promote breast cancer chemoresistance [ 132 ].…”

Section: The Roles Of Galectins In Cancer Metabolism Reprogrammingmentioning

confidence: 99%

“…Non-peptide compounds, such as OTX008, have been designed to target Gal-1 based on the effect of anginex [ 87 ], which has been found to serve as a therapeutic reagent for cancer and diabetic patients [ 40 , 87 , 182 , 183 , 184 ]. Treatment with BH3I-1 blocks the interaction between Tim-3 and Gal-9, which increases immune surveillance in colorectal cancer [ 84 ]. In addition, plant-derived galactomannans (known as DAVANAT) have been found to bind both Gal-1 and Gal-3, leading to CD8(+) tumor-infiltrating lymphocyte cytotoxicity [ 166 , 185 , 186 ].…”

Section: Available Inhibitors For Targeting Galectinsmentioning

confidence: 99%

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives

Chang

Chan

et al. 2021

Biomedicines

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Changes in cell growth and metabolism are affected by the surrounding environmental factors to adapt to the cell’s most appropriate growth model. However, abnormal cell metabolism is correlated with the occurrence of many diseases and is accompanied by changes in galectin (Gal) performance. Gals were found to be some of the master regulators of cell–cell interactions that reconstruct the microenvironment, and disordered expression of Gals is associated with multiple human metabolic-related diseases including cancer development. Cancer cells can interact with surrounding cells through Gals to create more suitable conditions that promote cancer cell aggressiveness. In this review, we organize the current understanding of Gals in a systematic way to dissect Gals’ effect on human disease, including how Gals’ dysregulated expression affects the tumor microenvironment’s metabolism and elucidating the mechanisms involved in Gal-mediated diseases. This information may shed light on a more precise understanding of how Gals regulate cell biology and facilitate the development of more effective therapeutic strategies for cancer treatment by targeting the Gal family.

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Mitochondrial Defunctionalization Supresses Tim-3-Galectin-9 Secretory Pathway in Human Colorectal Cancer Cells and Thus Can Possibly Affect Tumor Immune Escape

Cited by 10 publications

References 10 publications

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

The Tim-3-Galectin-9 Pathway and Its Regulatory Mechanisms in Human Breast Cancer

High Mobility Group Box 1 (HMGB1) Induces Toll-Like Receptor 4-Mediated Production of the Immunosuppressive Protein Galectin-9 in Human Cancer Cells

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives

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