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HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer.

ABSTRACT: Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.

SUBMITTER: Huang CY

PROVIDER: S-EPMC6158296 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer.

Huang Chih-Yang CY Chiang Shu-Fen SF Chen William Tzu-Liang WT Ke Tao-Wei TW Chen Tsung-Wei TW You Ying-Shu YS Lin Chen-Yu CY Chao K S Clifford KSC Huang Chih-Yang CY

Cell death & disease 20180926 10

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in condit ...[more]

PMID: 30258050

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Project description:The highly widespread and infiltrative nature of glioblastoma multiforme (GBM) makes complete surgical resection hard, causing high recurrence rate and poor patients' prognosis. However, the mechanism underlying GBM migration and invasion is still unclear. In this study, we investigated the role of a Ras-related protein Rab32 on GBM and uncovered its underlying molecular and subcellular mechanisms that contributed to GBM aggressiveness. The correlation of Rab32 expression with patient prognosis and tumor grade was investigated by public dataset analysis and clinical specimen validation. The effect of Rab32 on migration and invasion of GBM had been evaluated using wound healing assay, cell invasion assay, as well as protein analysis upon Rab32 manipulations. Mitochondrial dynamics of cells upon Rab32 alterations were detected by immunofluorescence staining and western blotting. Both the subcutaneous and intracranial xenograft tumor model were utilized to evaluate the effect of Rab32 on GBM in vivo. The expression level of Rab32 is significantly elevated in the GBM, especially in the most malignant mesenchymal subtype, and is positively correlated with tumor pathological grade and poor prognosis. Knockdown of Rab32 attenuated the capability of GBM's migration and invasion. It also suppressed the expression levels of invasion-related proteins (MMP2 and MMP9) as well as mesenchymal transition markers (N-cadherin, vimentin). Interestingly, Rab32 transported Drp1 to mitochondrial from the cytoplasm and modulated mitochondrial fission in an ERK1/2 signaling-dependent manner. Furthermore, silencing of Rab32 in vivo suppressed tumor malignancy via ERK/Drp1 axis. Rab32 regulates ERK1/2/Drp1-dependent mitochondrial fission and causes mesenchymal transition, promoting migration and invasion of GBM. It serves as a novel therapeutic target for GBM, especially for the most malignant mesenchymal subtype. Schematic of Rab32 promotes GBM aggressiveness via regulation of ERK/Drp1-mediated mitochondrial fission. Rab32 transports Drp1 from the cytoplasm to the mitochondria and recruits ERK1/2 to activate the ser616 site of Drp1, which in turn mediates mitochondrial fission and promotes mesenchymal transition, migration and invasion of GBM.

Project description:ObjectivesHigh-mobility group box-1 (HMGB1) and aberrant mitochondrial fission mediated by excessive activation of GTPase dynamin-related protein 1 (Drp1) have been found to be elevated in patients with pulmonary arterial hypertension (PAH) and critically implicated in PAH pathogenesis. However, it remains unknown whether Drp1-mediated mitochondrial fission and which downstream targets of mitochondrial fission mediate HMGB1-induced pulmonary arterial smooth muscle cells (PASMCs) proliferation and migration leading to vascular remodelling in PAH. This study aims to address these issues.MethodsPrimary cultured PASMCs were obtained from male Sprague-Dawley (SD) rats. We detected RNA levels by qRT-PCR, protein levels by Western blotting, cell proliferation by Cell Counting Kit-8 (CCK-8) and EdU incorporation assays, migration by wound healing and transwell assays. SD rats were injected with monocrotaline (MCT) to establish PAH. Hemodynamic parameters were measured by closed-chest right heart catheterization.ResultsHMGB1 increased Drp1 phosphorylation and Drp1-dependent mitochondrial fragmentation through extracellular signal-regulated kinases 1/2 (ERK1/2) signalling activation, and subsequently triggered autophagy activation, which further led to bone morphogenetic protein receptor 2 (BMPR2) lysosomal degradation and inhibitor of DNA binding 1 (Id1) downregulation, and eventually promoted PASMCs proliferation/migration. Inhibition of ERK1/2 cascade, knockdown of Drp1 or suppression of autophagy restored HMGB1-induced reductions of BMPR2 and Id1, and diminished HMGB1-induced PASMCs proliferation/migration. In addition, pharmacological inhibition of HMGB1 by glycyrrhizin, suppression of mitochondrial fission by Mdivi-1 or blockage of autophagy by chloroquine prevented PAH development in MCT-induced rats PAH model.ConclusionsHMGB1 promotes PASMCs proliferation/migration and pulmonary vascular remodelling by activating ERK1/2/Drp1/Autophagy/BMPR2/Id1 axis, suggesting that this cascade might be a potential novel target for management of PAH.

Dataset Information

HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer.

Publications

HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer.

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