Static Magnetic Field (0.2–0.4 T) Stimulates the Self‐Renewal Ability of Osteosarcoma Stem Cells Through Autophagic Degradation of Ferritin

Abstract

Static magnetic field (SMF) can alter cell fate decisions in many ways. However, the effects of SMF on cancer stem cells (CSCs) are little-known. In this particular study, we evaluate the biological effect of moderate-intensity SMF on osteosarcoma stem cells (OSCs) and try to clarify the underlying mechanisms of action. First, we demonstrated that prolonged exposure to SMF induced the proliferation and tumorsphere formation in K7M2 and MG63 OSCs. Moreover, SMF promoted the release of ferrous iron (Fe 2+ ) and provoked reactive oxygen species (ROS) in OSCs. Interestingly, SMF evidently triggered the autophagic degradation of ferritin, which is characterized by the activation of microtubule-associated protein 1 light chain 3 (LC3) and nuclear receptor coactivator 4 (NCOA4), and downregulation of ferritin heavy chain 1 (FTH1) in OSCs. Particularly, the colony-forming ability of K7M2 OSCs promoted by SMF was obviously abolished by using a small interfering RNA (siRNA) against NCOA4. Finally, treatment of the tumor-bearing mice with SMF did not affect the tumor volume or tumor mass, nor pulmonary metastasis of K7M2 OSCs, but the SMF-treated K7M2 OSCs caused a preference of pulmonary metastasis in a mouse model, which suggested that SMF might induce the metastatic characteristic of OSCs. Consequently, this paper demonstrates for the first time that the cumulative SMF exposure promoted the self-renewal ability of OSCs via autophagic degradation of ferritin, implying that ferritinophagy may be a potential molecular target for cancer. Bioelectromagnetics. 2021;42:371-383.

Magnetic Fields and Cancer: Epidemiology, Cellular Biology, and Theranostics

“…Moreover, the modulation in kinetic parameters of CAT, CYP-450, SOD, and MDA concentration and iNOS enzymes in response to ELF EMF [267][268][269] and the negligible effects on GPX [270] indicates an interaction between the ELF EMF and the enzymological system. SMF promoted the release of ferrous iron (Fe 2+ ) and induced the production of ROS in osteosarcoma stem cells [271]. Superoxide increased in the micronucleus and mitochondria with an exposure-response relationship and cytosolic superoxide increased at 10 µT in SH-SY5Y and C6 cells [272].…”

Cancer stem cells: a target for overcoming therapeutic resistance and relapse

“…Ferritinophagy is the process by which nuclear receptor coactivator 4 (NCOA4) releases the iron stored in ferritin to LIP and triggers ferroptosis 142 . A study conducted on osteosarcoma CSCs showed that exposure to a static magnetic field stimulates NCOA4-mediated ferritinophagy, promoting CSC proliferation and self-renewal 143 . Higher levels of glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11) protect esophageal CSCs from ferroptosis, which is induced by increased intracellular iron content.…”

Regulation of iron metabolism and ferroptosis in cancer stem cells

“…Similarly, the induction of ferritin autophagy mediated by NCOA4 increases the sensitivity of aggressive glioblastoma cells to ferroptosis ( 49 ). However, in a specific study, researchers evaluated the effect of long-term moderate-intensity static magnetic field (SMF) on osteosarcoma stem cells and found that exposure to SMF-activated NCOA4, induced ferritin autophagy, increased intracellular Fe 2+ levels, and promoted the self-renewal ability of osteosarcoma stem cells ( 50 ). Concerning these inconsistent results, we hypothesize that NCOA4’s effect on CSCs could rely on the base Fe 2+ level in LIP, which is sustained within certain limits.…”