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Although cytokine-based therapy is a promising tool to control the progression of esophageal cancer, low therapeutic responses largely compromise treatment efficacy through unidentified mechanisms. The goal of our study was to explore the roles of macrophage stimulating 1 (Mst1) and mitophagy in enhancing IL-24-based cytokine therapy in esophageal cancer. Our data demonstrated that IL-24 application promoted cancer death by inducing mitochondrial stress, as manifested by mitochondrial ROS overproduction, mitochondrial potential dissipation, cellular ATP deprivation and mitochondrial death activation. Overexpression of Mst1 enhanced IL-24-mediated mitochondrial damage and further augmented IL-24-induced death in esophageal cancer. Molecular investigations illustrated that the IL-24-activated mitochondrial response is accompanied by activation of mitophagy, a protective mechanism to attenuate mitochondrial damage. However, Mst1 overexpression inhibited mitophagy activity, which was achieved by inactivating the ERK-Mfn2 signaling pathway. The re-activation of mitophagy abolished the cancer-killing effects of Mst1 overexpression on esophageal cancer. Altogether, our data demonstrate that IL-24-related therapeutic resistance is associated with mitophagy activation. Mst1 overexpression inhibits mitophagy activity via suppressing the ERK-Mfn2 pathway, ultimately augmenting IL-24-inducd esophageal cancer death via enhanced mitochondrial stress.
This article was published in the following journal.
Name: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Immunotherapy has shown promising results in multiple malignancies. However, there are still significant challenges in cancer immunotherapy including the powerful immunosuppressive tumor microenvironm...
Long Non-Coding RNA (lncRNA) Growth Arrest Specific 5 (GAS5) Suppresses Esophageal Squamous Cell Carcinoma Cell Proliferation and Migration by Inactivating Phosphatidylinositol 3-kinase (PI3K)/AKT/Mammalian Target of Rapamycin (mTOR) Signaling Pathway.
BACKGROUND lncRNA GAS5 acts as a tumor-suppressor gene in various types of malignancies, but its involvement in esophageal cancer has not been well studied. MATERIAL AND METHODS A total of 112 patient...
Breast cancer is a prominent cause of death among women worldwide. Recent studies have demonstrated that artemisinin (ART) displays anti-tumor activity. Using a mouse breast cancer model, we investiga...
Macrophage polarization refers to the ability of these cells to adopt different functional phenotypes according to their environment. Mitogen-activated protein kinase phosphatase-1 (MKP-1) is known to...
The involvement of chronic inflammation in cholangiocarcinoma (CCA) progression is well established. Cluster of differentiation 47 (CD47) is mutually expressed in various cancers and serves as a prote...
The main purpose of this study is to test the safety of the dendritic cell/tumor fusion study vaccine in combination with a laboratory-made agent called Granulocyte Macrophage Colony Stimu...
Recently, the investigators have been screening for anti-atherogenic or pro-atherogenic amino acids (AAs) in the macrophage model system to better understand their role in atherogenesis. T...
A Pilot Study to Evaluate the Effects of Subcutaneously Administered Recombinant Human Granulocyte-Macrophage Colony Stimulating Factor in Pediatric HIV-Infected Patients With Neutropenia Secondary to Azidothymidine
To assess the safety and efficacy of subcutaneous sargramostim ( granulocyte-macrophage colony-stimulating factor; GM-CSF ) in increasing and maintaining the granulocyte count in HIV-infec...
The purpose of this study is to evaluate the correlation between M1/M2 phenotype of tumor associated macrophage (TAM) in lung cancer patients and clinical outcome.
To determine the safety, immunogenicity, biological activity, ad pharmacokinetics of sargramostim ( recombinant granulocyte-macrophage colony-stimulating factor; GM-CSF ) human granulocyte...
A mononuclear phagocyte colony-stimulating factor (M-CSF) synthesized by mesenchymal cells. The compound stimulates the survival, proliferation, and differentiation of hematopoietic cells of the monocyte-macrophage series. M-CSF is a disulfide-bonded glycoprotein dimer with a MW of 70 kDa. It binds to a specific high affinity receptor (RECEPTOR, MACROPHAGE COLONY-STIMULATING FACTOR).
Glycoproteins found in a subfraction of normal mammalian plasma and urine. They stimulate the proliferation of bone marrow cells in agar cultures and the formation of colonies of granulocytes and/or macrophages. The factors include INTERLEUKIN-3; (IL-3); GRANULOCYTE COLONY-STIMULATING FACTOR; (G-CSF); MACROPHAGE COLONY-STIMULATING FACTOR; (M-CSF); and GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR; (GM-CSF).
A receptor for MACROPHAGE COLONY-STIMULATING FACTOR encoded by the c-fms proto-oncogene (GENES, FMS). It contains an intrinsic protein-tyrosine kinase activity. When activated the receptor undergoes autophosphorylation, phosphorylation of down-stream signaling molecules and rapid down-regulation.
Receptors that bind and internalize the granulocyte-macrophage stimulating factor. Their MW is believed to be 84 kD. The most mature myelomonocytic cells, specifically human neutrophils, macrophages, and eosinophils, express the highest number of affinity receptors for this growth factor.
Granulocyte-macrophage colony-stimulating factors prepared by recombinant DNA technology.
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Cytokine Tumour Necrosis Factor (TNF)
TNF is a compound that is classified as a cytokine which plays a central role in the cellular mechanisms of apoptosis or cell death. However, there are a number of different kinds of TNF, just under twenty, but the family of molecules have very similar a...
Cancer is not just one disease but many diseases. There are more than 100 different types of cancer. Most cancers are named for the organ or type of cell in which they start - for example, cancer that begins in the colon is called colon cancer; cancer th...