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Lipid droplets and ferritin heavy chain: a devilish liaison in human cancer cell radioresistance.

ABSTRACT: Although much progress has been made in cancer treatment, the molecular mechanisms underlying cancer radioresistance (RR) as well as the biological signatures of radioresistant cancer cells still need to be clarified. In this regard, we discovered that breast, bladder, lung, neuroglioma, and prostate 6 Gy X-ray resistant cancer cells were characterized by an increase of lipid droplet (LD) number and that the cells containing highest LDs showed the highest clonogenic potential after irradiation. Moreover, we observed that LD content was tightly connected with the iron metabolism and in particular with the presence of the ferritin heavy chain (FTH1). In fact, breast and lung cancer cells silenced for the FTH1 gene showed a reduction in the LD numbers and, by consequence, became radiosensitive. FTH1 overexpression as well as iron-chelating treatment by Deferoxamine were able to restore the LD amount and RR. Overall, these results provide evidence of a novel mechanism behind RR in which LDs and FTH1 are tightly connected to each other, a synergistic effect that might be worth deeply investigating in order to make cancer cells more radiosensitive and improve the efficacy of radiation treatments.

SUBMITTER: Tirinato L

PROVIDER: S-EPMC8497056 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Lipid droplets and ferritin heavy chain: a devilish liaison in human cancer cell radioresistance.

Tirinato Luca L Marafioti Maria Grazia MG Pagliari Francesca F Jansen Jeannette J Aversa Ilenia I Hanley Rachel R Nisticò Clelia C Garcia-Calderón Daniel D Genard Geraldine G Guerreiro Joana Filipa JF Costanzo Francesco Saverio FS Seco Joao J

eLife 20210909

Although much progress has been made in cancer treatment, the molecular mechanisms underlying cancer radioresistance (RR) as well as the biological signatures of radioresistant cancer cells still need to be clarified. In this regard, we discovered that breast, bladder, lung, neuroglioma, and prostate 6 Gy X-ray resistant cancer cells were characterized by an increase of lipid droplet (LD) number and that the cells containing highest LDs showed the highest clonogenic potential after irradiation. ...[more]

PMID: 34499029

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Project description:Background: Iron overload can accelerate the accumulation of lipid oxides and contribute to the progression of atherosclerosis. Ferritin heavy chain (FT-H) exhibits oxidase activity, which inhibits the toxicity of ferrous ions and reduces oxidative damage. We investigated the effect of the intraperitoneal injection of FT-H on the progression of atherosclerosis in APOE-knockout mice (Apo-E(-/-) mice). Methods: All mice were fed on a high-fat diet. After 10 weeks, the mice were divided into an injection group (n = 4) and a control group (n = 4). The injection group was injected intraperitoneally with FT-H (50 mg/kg, once a week), and the control group was treated with PBS buffer (at an equal volume to the injection group, once a week). After 10 weeks of intervention, MRI of the aortas was performed. Then, the animals were sacrificed, and tissues were taken. Hematoxylin-eosin (HE) staining was used for histomorphometry, Masson staining was used to quantify the collagen content in the arteries, Prussian blue staining was used to visualize iron deposition in the arteries, and MRI was used to analyze the structure of the aorta in vivo. Immunohistochemistry was performed to detect the expression of MCP-1, MMP-2, MMP-9, FT-H, FT-L, TfR1, NRF-2 and GPX-4. Results: The serological results showed that the injection group had lower levels of glucose (Glu), triacylglycerol (TG), cholesterol (CHO), low-density lipoprotein-C (LDL-C) and malondialdehyde (MDA) (p = 0.0058, p = 0.0098, p = 0.0019, p = 0.0368 and p = 0.0025, respectively), and their serum ferritin (SF) and superoxide dismutase (SOD) levels were higher (p = 0.0004 and p < 0.0001). The Masson staining and MRI results showed that the injection group had less collagen deposition (p = 0.0226), a larger arterial lumen area and arterial volume (p = 0.0006 and p = 0.0005), thinner arterial wall thickness (p = 0.0013) and a more stable arterial plaque structure (p < 0.0001). The immunohistochemical results showed reduced expression of FT-H, FT-L, TfR1, MMP-2, MMP-9, MCP-1 and NRF-2 in the injection group (p = 0.0054, p = 0.0242, p = 0.0221, p = 0.0477, p = 0.0131, p = 0.0435 and p = 0.0179). Prussian blue staining showed that the area of iron-positive areas in the aortic plaques of the control group was larger than that of injected group. The expression of GPX-4 was lower in the control group than in the injection group (p = 0.016). Conclusions: The intraperitoneal administration of FT-H to Apo-E(-/-) mice resulted in lower blood glucose and lipid levels; reduced iron and iron metabolism protein deposition in the aorta; reduced indices of their ferroptosis, oxidation and inflammatory aggregation; and reduced collagen deposition in the aorta, which delayed the process of aortic atherosclerosis in mice.

Dataset Information

Lipid droplets and ferritin heavy chain: a devilish liaison in human cancer cell radioresistance.

Publications

Lipid droplets and ferritin heavy chain: a devilish liaison in human cancer cell radioresistance.

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