Nitric Oxide-Releasing Drug Glyceryl Trinitrate Targets JAK2/STAT3 Signaling, Migration and Invasion of Triple-Negative Breast Cancer Cells

Bouaouiche, Sarra; Ghione, S; Sghaier, Randa; Burgy, Olivier; Racoeur, Cindy; Dérangère, Valentin; Bettaı̈eb, Ali; Plenchette, Stéphanie

doi:10.3390/ijms22168449

Cited by 13 publications

(13 citation statements)

References 53 publications

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“…SCF/c-Kit axis regulates the migration of colorectal cancer [ 31 ] and cervical cancer [ 20 ], but to our knowledge this is the first report showing that c-Kit mediates TNBC cell migration. It has been demonstrated that the PI3K/Akt [ 32 ] and JAK2/STAT3 [ 33 ] cascades are important regulators of TNBC cell migration. Correspondingly, we observed that SCF stimulation induced the activation of Akt and STAT3 in migrating cells.…”

Section: Discussionmentioning

confidence: 99%

c-Kit Induces Migration of Triple-Negative Breast Cancer Cells and Is a Promising Target for Tyrosine Kinase Inhibitor Treatment

López-Mejía

Tallabs-Utrilla

Salazar-Sojo

et al. 2022

IJMS

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Triple-negative breast cancer (TNBC) is associated with a poor prognosis and the absence of targeted therapy. c-Kit, a receptor tyrosine kinase (RTK), is considered a molecular target for anticancer drugs. Tyrosine kinase inhibitors (TKIs) recognizing c-Kit are used for the treatment of c-Kit-expressing tumors. However, the expression, function, and therapeutic potential of c-Kit have been little explored in TNBC. Here, we studied the expression and effects of c-Kit in TNBC through in vitro and in silico analysis, and evaluated the response to TKIs targeting c-Kit. Analysis of TNBC cells showed the expression of functional c-Kit at the cell membrane. The stimulation of c-Kit with its ligand induced the activation of STAT3, Akt, and ERK1/2, increasing cell migration, but had no effect on cell proliferation or response to Doxorubicin. Analysis of public datasets showed that the expression of c-Kit in tumors was not associated with patient survival. Finally, TNBC cells were susceptible to TKIs, in particular the effect of Nilotinib was stronger than Doxorubicin in all cell lines. In conclusion, TNBC cells express functional c-Kit, which is a targetable molecule, and show a strong response to Nilotinib that may be considered a candidate drug for the treatment of TNBC.

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Section: Discussionmentioning

confidence: 99%

c-Kit Induces Migration of Triple-Negative Breast Cancer Cells and Is a Promising Target for Tyrosine Kinase Inhibitor Treatment

López-Mejía

Tallabs-Utrilla

Salazar-Sojo

et al. 2022

IJMS

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“…Glyceryl trinitrate inhibits JAK2 through s-nitrosylation to suppress IL-6-induced migration and invasion in TNBC cells. Additionally, glyceryl trinitrate infusion decreases lung metastatic lesions in a TNBC syngeneic mouse model ( 147 ). Pentadecanoic acid suppresses the CSC subpopulation through inhibition of IL-6/JAK/STAT3 signaling and increases apoptosis in ER+ breast cancer cell line; however, the exact mechanism remains unknown ( 148 ).…”

Section: Current Therapeutic Applications Of Il-6 Signaling In Breast...mentioning

confidence: 99%

IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment

et al. 2022

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Breast cancer is the most commonly diagnosed cancer in women. Metastasis is the primary cause of mortality for breast cancer patients. Multiple mechanisms underlie breast cancer metastatic dissemination, including the interleukin-6 (IL-6)-mediated signaling pathway. IL-6 is a pleiotropic cytokine that plays an important role in multiple physiological processes including cell proliferation, immune surveillance, acute inflammation, metabolism, and bone remodeling. IL-6 binds to the IL-6 receptor (IL-6Rα) which subsequently binds to the glycoprotein 130 (gp130) receptor creating a signal transducing hexameric receptor complex. Janus kinases (JAKs) are recruited and activated; activated JAKs, in turn, phosphorylate signal transducer and activator of transcription 3 (STAT3) for activation, leading to gene regulation. Constitutively active IL-6/JAK/STAT3 signaling drives cancer cell proliferation and invasiveness while suppressing apoptosis, and STAT3 enhances IL-6 signaling to promote a vicious inflammatory loop. Aberrant expression of IL-6 occurs in multiple cancer types and is associated with poor clinical prognosis and metastasis. In breast cancer, the IL-6 pathway is frequently activated, which can promote breast cancer metastasis while simultaneously suppressing the anti-tumor immune response. Given these important roles in human cancers, multiple components of the IL-6 pathway are promising targets for cancer therapeutics and are currently being evaluated preclinically and clinically for breast cancer. This review covers the current biological understanding of the IL-6 signaling pathway and its impact on breast cancer metastasis, as well as, therapeutic interventions that target components of the IL-6 pathway including: IL-6, IL-6Rα, gp130 receptor, JAKs, and STAT3.

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“…Invasion was also significantly lower in CM from unirradiated spheroids co-cultured with macrophages. Previous studies have shown that neutralization of IL-6 reduces invasiveness of 4T1 cells and that macrophage-derived IL-6 contributes to tumor cell migratory ability 37,38 . However, we are the first to show the dependence of 4T1 invasiveness on IL-6 secreted from stromal-macrophage interactions.…”

Section: Resultsmentioning

confidence: 99%

Irradiated Mammary Spheroids Elucidate Mechanisms of Macrophage-Mediated Breast Cancer Recurrence

Herman

Lin

Questell

et al. 2022

Preprint

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While most patients with triple negative breast cancer receive radiotherapy to improve outcomes, a significant subset of patients continue to experience recurrence. Macrophage infiltration into radiation-damaged sites has been shown to promote breast cancer recurrence in pre-clinical models. However, the mechanisms that drive recurrence are unknown. Here, we developed a novel spheroid model to evaluate macrophage-mediated tumor cell recruitment. We first characterized infiltrating macrophage phenotypes into irradiated mammary tissue to inform our model. We then established spheroids consisting of fibroblasts isolated from mouse mammary glands. We observed that tumor cell motility toward irradiated spheroids was enhanced in the presence of a 2:1 ratio of pro-healing:pro-inflammatory macrophages. We also measured a significant increase in interleukin 6 (IL-6) secretion after irradiation both in vivo and in our model. This secretion increased tumor cell invasiveness, and invasion was mitigated by neutralizing IL-6. Taken together, our work suggests that interactions between infiltrating macrophages and damaged stromal cells facilitates breast cancer recurrence through IL-6 signaling.

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Nitric Oxide-Releasing Drug Glyceryl Trinitrate Targets JAK2/STAT3 Signaling, Migration and Invasion of Triple-Negative Breast Cancer Cells

Cited by 13 publications

References 53 publications

c-Kit Induces Migration of Triple-Negative Breast Cancer Cells and Is a Promising Target for Tyrosine Kinase Inhibitor Treatment

c-Kit Induces Migration of Triple-Negative Breast Cancer Cells and Is a Promising Target for Tyrosine Kinase Inhibitor Treatment

IL-6/JAK/STAT3 Signaling in Breast Cancer Metastasis: Biology and Treatment

Irradiated Mammary Spheroids Elucidate Mechanisms of Macrophage-Mediated Breast Cancer Recurrence

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