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 which might be worth deeply investigating in order to make cancer cells more radiosensitive and improve the efficacy of radiation treatments.

Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation

“…It has been shown that RR cancer cells can activate several antioxidant pathways in order to reduce ROS generated by radiation therapy. In this context, LDs can play a crucial role to avoid lipotoxicity and retain the cell homeostasis, favoring DNA repair and promoting cell survival [39,[42][43][44]. In our conditions, while MCF7 cells were presumably able to deal with the oxidative stress induced shortly after ionizing radiation, they showed increased ROS levels after 72 h of PF-06424439 which resulted further increased 72 h after IR both in cells only pretreated with PF-06424439 and in cells subjected to combined treatments.…”

“…Furthermore, some evidences demonstrated that the LD amount is proportional to the degree of tumorigenicity in breast cancer cell lines [21], sustaining that the aberrant accumulation of these organelles represents one of the main features of BCSCs [24]. Additionally, we have recently shown that in different cancer tissues, including breast, the most radioresistant cancer cells were characterized by a higher LD expression, and that the LD content was tightly regulated by the ferritin heavy chain 1 (FTH1) [39].…”

Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage

“…LDs have now been suggested to be involved in all processes of cancer development, including initiation, promotion, and progression [ 111 ]. The hypotheses regarding LD function in cancer cells are numerous, i.e., promoting tumor proliferation [ 153 , 154 , 155 ], driving epithelial–mesenchymal transition (EMT) [ 115 , 156 , 157 ], mediating radio-resistance [ 158 , 159 ] and chemo-resistance [ 160 , 161 , 162 , 163 ], maintaining cancer cell stemness [ 164 , 165 , 166 ], and avoiding immune destruction [ 167 , 168 , 169 ]. Nevertheless, these hypotheses need to be experimentally validated.…”

Deciphering the Biological Effects of Radiotherapy in Cancer Cells

“…Mechanistically, acetyl-CoA, which is one of the main metabolites of FAO, upregulates the expression of CD47 by acetylating RelA K310 [ 47 ]. It is also notable that the crosstalk between lipid droplets and iron metabolism makes cancer cells more radioresistant [ 50 ]. In hepatocellular carcinoma (HCC) cells, the integration of glucose and cardiolipin anabolism, which is regulated by the mTORC1/HIF-1α/SREBP1 axis, promotes resistance to radiation by repressing cytochrome c extrusion [ 51 ].…”