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GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2-c-Fos-LIF signaling.

ABSTRACT: Growth differentiation factor 15 (GDF15), a member of the transforming growth factor ? family, is associated with tumor progression, metastasis, and cell apoptosis. However, controversy persists regarding the role of GDF15 in different tumor types, and its function in glioma stem cells (GSCs) remains unknown. Here, we report that GDF15 promotes the GSC-like phenotype in GSC-like cells (GSCLCs) through the activation of leukemia inhibitor factor (LIF)-STAT3 signaling. Mechanistically, GDF15 was found to upregulate expression of the transcription factor c-Fos, which binds to the LIF promoter, leading to enhanced transcription of LIF in GSCLCs. Furthermore, GDF15 may activate the ERK1/2 signaling pathway in GSCLCs, and the upregulation of LIF expression and the GSC-like phenotype was dependent on ERK1/2 signaling. In addition, the small immunomodulator imiquimod induced GDF15 expression, which in turn activated the LIF-STAT3 pathway and subsequently promoted the GSC-like phenotype in GSCLCs. Thus, our results demonstrate that GDF15 can act as a proliferative and pro-stemness factor for GSCs, and therefore, it may represent a potential therapeutic target in glioma treatment.

SUBMITTER: Zhu S

PROVIDER: S-EPMC7801449 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2-c-Fos-LIF signaling.

Zhu Shan S Yang Ning N Guan Yi Y Wang Xue X Zang Guoxia G Lv Xinping X Deng Shuanglin S Wang Wan W Li Tete T Chen Jingtao J

Cell death discovery 20210111 1

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor β family, is associated with tumor progression, metastasis, and cell apoptosis. However, controversy persists regarding the role of GDF15 in different tumor types, and its function in glioma stem cells (GSCs) remains unknown. Here, we report that GDF15 promotes the GSC-like phenotype in GSC-like cells (GSCLCs) through the activation of leukemia inhibitor factor (LIF)-STAT3 signaling. Mechanistically, GDF15 was f ...[more]

PMID: 33431816

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Project description:BACKGROUND:Growth differentiation factor 15 (GDF15) is a member of the TGF-? superfamily, and evidence suggests that a substantial amount of GDF15 is secreted in various human cancers, such as ovarian cancer, prostate cancer, and breast cancer, among others. However, the function of GDF15 in cervical cancer has not yet been reported. METHODS:Immunohistochemistry was used to detect GDF15 expression in normal cervix and in different cervical cancer lesions. Cell growth curves, MTT, tumor formation assays and flow cytometry were utilized to observe the effects of ectopic GDF15 expression on the proliferation and cell cycle of cervical cancer cells. Real-time PCR, western blotting and immunoprecipitation assays were conducted to measure the expression of genes related to the cell cycle and the PI3K/AKT and MAPK/ERK signaling pathways. A chromatin immunoprecipitation assay was performed to confirm whether C-myc bound to a specific region of the GDF15 promoter. Inhibitor treatment and immunoprecipitation assays were employed to identify the association between GDF15 and ErbB2. RESULTS:GDF15 expression gradually increased during the progression of cervical carcinogenesis. GDF15 promoted cervical cancer cell proliferation via exogenous rhGDF15 treatment or the use of gene editing technology in vitro and in vivo and significantly accelerated the cell cycle transition from G0/G1 to S phase. The expression of p-ErbB2, p-AKT1, p-Erk1/2, CyclinD1 and CyclinE1 was up-regulated and the expression of p21 was down-regulated in GDF15-overexpressing and rhGDF15-treated cervical cancer cells. C-myc trans-activated GDF15 expression by binding to the E-box motifs in the promoter of GDF15 and contributed to the positive feedback of GDF15/C-myc/GDF15. Furthermore, GDF15 bound to ErbB2 in a protein complex in cervical cancer cells. CONCLUSIONS:Our data demonstrated that GDF15 promoted the proliferation of cervical cancer cells via the up-regulation of CyclinD1 and CyclinE1 and the down-regulation of p21 through both the PI3K/AKT and MAPK/ERK signaling pathways in a complex with ErbB2.

Project description:IntroductionGlioblastoma (GBM) is the most common primary malignant brain tumor in humans and, even with aggressive treatment that includes surgical resection, radiation (IR), and chemotherapy administration, prognosis is poor due to tumor recurrence. There is evidence that within GBMs a small number of glioma stem-like cells (GSLCs) exist, which are thought to be therapy resistant and are thus capable of repopulating a tumor after treatment. Like most cancers, GBMs largely employ aerobic glycolysis to create ATP, a phenomenon known as the Warburg Effect. There is no consensus on the metabolic characteristics of cancer stem cells. GSLCs have been shown to rely more heavily on oxidative phosphorylation, but there is also evidence that cancer stem cells can adapt their metabolism by fluctuating between energy pathways or acquiring intermediate metabolic phenotypes. We hypothesized that the metabolism of GSLCs differs from that of differentiated GBM tumor cell lines, and that the steady state metabolism would be differentially altered following radiation treatment.Materials and methodsWe evaluated the oxygen consumption rate, extracellular acidification rate, and metabolic enzyme levels of GBM cell lines and GSLCs before and after irradiation using extracellular flux assays. We also measured absolute metabolite levels in these cells via mass spectroscopy with and without radiation treatment.ResultsGSLCs were found to be significantly more quiescent in comparison to adherent GBM cell lines, highlighted by lower glycolytic and maximal respiratory capacities as well as lower oxygen consumption and extracellular acidification rates. Analysis of individual metabolite concentrations revealed lower total metabolite concentrations overall but also elevated levels of metabolites in different energy pathways for GSLCs compared to GBM cell lines. Additionally, the metabolism of both GSLCs and GBM cell lines were found to be altered by IR.ConclusionsWhile there is not one metabolic alteration that distinguishes irradiated GSLC metabolism from that of GBM cell lines, therapies targeting more metabolically quiescent tumor cells and thus the resistant GSLC population may increase a cancer's sensitivity to radiotherapy.

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GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2-c-Fos-LIF signaling.

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GDF15 promotes glioma stem cell-like phenotype via regulation of ERK1/2-c-Fos-LIF signaling.

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