Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism

Dahlem, Charlotte; Siow, Wei Xiong; Lopatniuk, Maria; Tse, William Ka Fai; Kessler, Sonja M.; Kirsch, Sarah; Hoppstädter, Jessica; Vollmar, Angelika M.; Müller, Rolf; Luzhetskyy, Andriy; Bartel, Karin; Kiemer, Alexandra K.

doi:10.3390/cancers12051288

Cited by 30 publications

(39 citation statements)

References 53 publications

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“…1A ). Macrophage polarization is characterized by distinct morphological features ( 25 ). Using H&E staining, it was identified that TAM(Ca) and TAM(CAF) exhibited an elongated morphology, which was similar to that of M2-polarized macrophages.…”

Section: Resultsmentioning

confidence: 99%

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

et al. 2021

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Targeting the tumor stroma is an important strategy in cancer treatment. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are two main components in the tumor microenvironment (TME) in hepatocellular carcinoma (HCC), which can promote tumor progression. Plasminogen activator inhibitor-1 (PAI-1) upregulation in HCC is predictive of unfavorable tumor behavior and prognosis. However, the crosstalk between cancer cells, TAMs and CAFs, and the functions of PAI-1 in HCC remain to be fully investigated. In the present study, macrophage polarization and key paracrine factors were assessed during their interactions with CAFs and cancer cells. Cell proliferation, wound healing and Transwell and Matrigel assays were used to investigate the malignant behavior of HCC cells in vitro. It was found that cancer cells and CAFs induced the M2 polarization of TAMs by upregulating the mRNA expression levels of CD163 and CD206, and downregulating IL-6 mRNA expression and secretion in the macrophages. Both TAMs derived from cancer cells and CAFs promoted HCC cell proliferation and invasion. Furthermore, PAI-1 expression was upregulated in TAMs after being stimulated with CAF-conditioned medium and promoted the malignant behavior of the HCC cells by mediating epithelial-mesenchymal transition. CAFs were the main producer of C-X-C motif chemokine ligand 12 (CXCL12) in the TME and CXCL12 contributed to the induction of PAI-1 secretion in TAMs. In conclusion, the results of the present study suggested that CAFs promoted the M2 polarization of macrophages and induced PAI-1 secretion via CXCL12. Furthermore, it was found that PAI-1 produced by the TAMs enhanced the malignant behavior of the HCC cells. Therefore, these factors may be targets for inhibiting the crosstalk between tumor cells, CAFs and TAMs.

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Section: Resultsmentioning

confidence: 99%

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

et al. 2021

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“…Monocytes were isolated and polarized as previously described [ 35 , 36 ]. In brief, peripheral blood mononuclear cells (PBMCs) were isolated from buffy coats by density gradient centrifugation using Lymphocyte Separation Medium 1077 (#C-44010, PromoCell, Heidelberg, Germany) and LeucoSEP tubes (#227290, Greiner Bio-One, Kremsmünster, Austria).…”

Section: Methodsmentioning

confidence: 99%

Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages

et al. 2021

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Background Based on reports on elevated cholesterol levels in cancer cells, strategies to lower cholesterol synthesis have been suggested as an antitumour strategy. However, cholesterol depletion has also been shown to induce tumour-promoting actions in tumour-associated macrophages (TAMs). Methods We performed lipidomic and transcriptomic analyses of human lung cancer material. To assess whether the TAM phenotype is shaped by secreted factors produced by tumour cells, primary human monocyte-derived macrophages were polarized towards a TAM-like phenotype using tumour cell-conditioned medium. Findings Lipidomic analysis of lung adenocarcinoma (n=29) and adjacent non-tumour tissues (n=22) revealed a significant accumulation of free cholesterol and cholesteryl esters within the tumour tissue. In contrast, cholesterol levels were reduced in TAMs isolated from lung adenocarcinoma tissues when compared with alveolar macrophages (AMs) obtained from adjacent non-tumour tissues. Bulk-RNA-Seq revealed that genes involved in cholesterol biosynthesis and metabolism were downregulated in TAMs, while cholesterol efflux transporters were upregulated. In vitro polarized TAM-like macrophages showed an attenuated lipogenic gene expression signature and exhibited lower cholesterol levels compared with non-polarized macrophages. A genome-wide comparison by bulk RNA-Seq confirmed a high similarity of ex vivo TAMs and in vitro TAM-like macrophages. Modulation of intracellular cholesterol levels by either starving, cholesterol depletion, or efflux transporter inhibition indicated that cholesterol distinctly shapes macrophage gene expression. Interpretation Our data show an opposite dysregulation of cholesterol homeostasis in tumour tissue vs. TAMs. Polarization of in vitro differentiated macrophages by tumour cell-conditioned medium recapitulates key features of ex vivo TAMs.

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“…Thioholgamide A and B were initially isolated from a mangrove-derived streptomycete, Streptomyces malaysiense MUSC 136 T, and possess cytotoxic activities against cancer cell lines [75,76] . Recently, a research group in Germany has published an article studying the mechanisms involved behind the cytotoxic and anti-proliferative activities of thioholgamide A [75,77] . The team showed that thioholgamide A induces apoptosis via caspase 3 and PARP cleavage (at concentrations comparable to staurosporine) [77] .…”

Section: Data Descriptionmentioning

confidence: 99%

“…Recently, a research group in Germany has published an article studying the mechanisms involved behind the cytotoxic and anti-proliferative activities of thioholgamide A [75,77] . The team showed that thioholgamide A induces apoptosis via caspase 3 and PARP cleavage (at concentrations comparable to staurosporine) [77] . Furthermore, it appears that thioholgamide A inhibits oxidative phosphorylation in tumor cells without displaying much toxicity towards nontumorigenic cells and zebrafish embryos, thus making the compound an appealing candidate that to be developed as anti-cancer therapeutics.…”

Section: Data Descriptionmentioning

confidence: 99%

Whole-genome sequence of bioactive streptomycete derived from mangrove forest in Malaysia, Streptomyces sp. MUSC 14

Ser¹,

Tan²,

Tan³

et al. 2021

Prog Micobes Mol Biol

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The contribution of streptomycetes to human health is undeniably important and significant, given that these filamentous microbes can produce interesting compounds that can be used to cure deadly infections and even cancer. Isolated from the east coast of Peninsular Malaysia, Streptomyces sp. MUSC 14 has shown significant antioxidant capacity. The current study explores the genomic potential of MUSC 14 via a genome mining approach. The genome size of MUSC 14 is 10,274,825 bp with G + C content of 71.3 %. AntiSMASH analysis revealed a total of nine biosynthetic gene clusters (with more than 80 % similarities to known gene clusters). This information serves as an important foundation for subsequent studies, particularly the purification and isolation of bioactive compounds by genetic manipulation techniques.

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Thioholgamide A, a New Anti-Proliferative Anti-Tumor Agent, Modulates Macrophage Polarization and Metabolism

Cited by 30 publications

References 53 publications

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

Dysregulation of cholesterol homeostasis in human lung cancer tissue and tumour-associated macrophages

Whole-genome sequence of bioactive streptomycete derived from mangrove forest in Malaysia, Streptomyces sp. MUSC 14

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