β-Phenethyl Isothiocyanate Induces Cell Death in Human Osteosarcoma through Altering Iron Metabolism, Disturbing the Redox Balance, and Activating the MAPK Signaling Pathway

Abstract

Osteosarcoma is the most common primary malignancy of the skeleton in children and adults. The outcomes of people with osteosarcomas are unsatisfied. β-Phenethyl isothiocyanate (PEITC) exhibits chemoprevention and chemotherapeutic activities against many human cancers. The molecular mechanism underlying its action on osteosarcoma is still unknown. This study was aimed at investigating the effect of PEITC on human osteosarcoma both in vitro and in vivo. The results showed that PEITC reduced cell viability, inhibited proliferation, and caused G2/M cell cycle arrest in four human osteosarcoma cell lines (MNNG/HOS, U-2 OS, MG-63, and 143B). Then, we found that PEITC altered iron metabolism related to the processes of iron import, storage, and export, which resulted in increased labile iron. Expectedly, PEITC caused oxidative stress as a consequence of GSH depletion-inducing ROS generation and lipid peroxidation. Multiple cell death modalities, including ferroptosis, apoptosis, and autophagy, were triggered in human osteosarcoma cells. Three MAPKs (ERK, p38, and JNK) were all activated after PEITC treatment; however, they presented different responses among the four human osteosarcoma cell lines. ROS generation was proved to be the major cause of PEITC-induced decreased proliferative potential, altered iron metabolism, cell death, and activated MAPKs in human osteosarcoma cells. In addition, PEITC also significantly delayed tumor growth in a xenograft osteosarcoma mouse model with a 30 mg/kg administration dose. In conclusion, this study reveals that PEITC simultaneously triggers ferroptosis, apoptosis, and autophagy in human osteosarcoma cells by inducing oxidative stress.

Development and validation of a ferroptosis-related lncRNAs prognosis signature in colon cancer

“…Pathway in cancer, mTOR signaling pathway, MAPK signaling pathway, VEGF signaling pathway, and JAK-STAT signaling pathway were significantly enriched in the high-risk group (P < 0.05, FDR<0.25). Previous studies have been confirmed that mTOR-, MAPK-and JAK-STAT signaling pathway was involved in the regulation of ferroptosis in diverse diseases [27][28][29]. Zhang et al identified that mTOR signaling pathway was activated in COAD, leading to lethal ROS accumulation and ferroptosis [30,31].…”

Targeting ferroptosis in osteosarcoma

“…As the key pathway in the mechanism associated with OS, MAPK is decisive for the balanced relationship between tumour cell viability and mortality [39] . The recent study reported significant activation of MAPK followed by high-level phosphorylation of ERK, p38 and JNK in OS cells undergoing ferroptosis, and confirmed that the ROS/MAPK pathway is involved in the ferroptosis mechanism of OS cells with lipid ROS production being the main cause of MAPK activation [40] . Besides, numerous emerging anticancer substances have exhibited varying degrees of cancer inhibition effect in vitro and in vivo OS assays by mobilising the lipid ROS/MAPK pathway [41] , [42] .…”

Identification of Seven Novel Ferroptosis-Related Long Non - Coding RNA Signatures as a Diagnostic Biomarker for Acute Myeloid Leukemia

“…The AML, VEGF, and MAPK signaling pathways were signi cantly enriched in the high-risk group. Previous studies have con rmed that VEGF and MAPK signaling pathways are involved in the regulation of ferroptosis in various diseases [20,21]. In addition, the glutathione metabolism pathway was signi cantly enriched in the highrisk group.…”