Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells

Ren, Tianhao; Huang, Ju; Sun, Wei; Wang, Guangze; Wu, Yue; Jiang, Zewei; Lv, Yingshuai; Wu, Guang; Cao, Jianhua; Liu, Min; Gu, Haihua

doi:10.3389/fphar.2022.1071946

Cited by 11 publications

(8 citation statements)

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“…Among these drugs whose sensitivity is related to HIC1 expression, zoledronate, and trametinib have been reported to be associated with ferroptosis. In osteosarcoma, zoledronic acid can induce ferroptosis by decreasing ubiquinone and upregulating the expression of HMOX1 or cytochrome P450 oxidoreductase (POR) ( 50 , 51 ). Besides, zoledronic acid also induced ferroptosis in osteoclasts by suppressing ubiquitination and degradation of p53 through FBXO9 ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis-related gene HIC1 in the prediction of the prognosis and immunotherapeutic efficacy with immunological activity

Lin

Tang

et al. 2023

Front. Immunol.

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BackgroundHypermethylated in Cancer 1 (HIC1) was originally confirmed as a tumor suppressor and has been found to be hypermethylated in human cancers. Although growing evidence has supported the critical roles of HIC1 in cancer initiation and development, its roles in tumor immune microenvironment and immunotherapy are still unclear, and no comprehensive pan-cancer analysis of HIC1 has been conducted.MethodsHIC1 expression in pan-cancer, and differential HIC1 expression between tumor and normal samples were investigated. Immunohistochemistry (IHC) was employed to validate HIC1 expression in different cancers by our clinical cohorts, including lung cancer, sarcoma (SARC), breast cancer, and kidney renal clear cell carcinoma (KIRC). The prognostic value of HIC1 was illustrated by Kaplan-Meier curves and univariate Cox analysis, followed by the genetic alteration analysis of HIC1 in pan-cancer. Gene Set Enrichment Analysis (GSEA) was conducted to illustrate the signaling pathways and biological functions of HIC1. The correlations between HIC1 and tumor mutation burden (TMB), microsatellite instability (MSI), and the immunotherapy efficacy of PD-1/PD-L1 inhibitors were analyzed by Spearman correlation analysis. Drug sensitivity analysis of HIC1 was performed by extracting data from the CellMiner™ database.ResultsHIC1 expression was abnormally expressed in most cancers, and remarkable associations between HIC1 expression and prognostic outcomes of patients in pan-cancer were detected. HIC1 was significantly correlated with T cells, macrophages, and mast cell infiltration in different cancers. Moreover, GSEA revealed that HIC1 was significantly involved in immune-related biological functions and signaling pathways. There was a close relationship of HIC1 with TMB and MSI in different cancers. Furthermore, the most exciting finding was that HIC1 expression was significantly correlated with the response to PD-1/PD-L1 inhibitors in cancer treatment. We also found that HIC1 was significantly correlated with the sensitivity of several anti-cancer drugs, such as axitinib, batracylin, and nelarabine. Finally, our clinical cohorts further validated the expression pattern of HIC1 in cancers.ConclusionsOur investigation provided an integrative understanding of the clinicopathological significance and functional roles of HIC1 in pan-cancer. Our findings suggested that HIC1 can function as a potential biomarker for predicting the prognosis, immunotherapy efficacy, and drug sensitivity with immunological activity in cancers.

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Section: Discussionmentioning

confidence: 99%

Ferroptosis-related gene HIC1 in the prediction of the prognosis and immunotherapeutic efficacy with immunological activity

Lin

Tang

et al. 2023

Front. Immunol.

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“…(rhabdomyosarcoma) [ 147 , 158 ] Sulfasalazine (SAS) SLC7A11 inhibitor GSH ↓ K7M2 (murine osteosarcoma) [ 153 ] Theaflavin-3,3'-digallate (TF3) Down-regulating FTH and GPX4, GSH consumption Fe 2+ ↑, GSH ↓, GPX4 ↓ ROS ↑, MDA ↑ MG63. HOS, hFOB1.19 (osteosarcoma) [ 159 ] Tirapazamine (under hypoxia) SLC7A11 and GPX4 inhibitor; up-regulating p53 Fe 2+ ↑, GSH ↓, GPX4 ↓ 143B, U2OS, MNNG/Hos (osteosarcoma) [ 160 ] Ursolic acid Ferritin autophagy Fe 2+ ↑ 143 B, HOS (osteosarcoma) [ 161 ] Zoledronic acid Up-regulating POR, down-regulating CoQ10, HMOX1 overexpression ROS ↑, lipid peroxides ↑ Human osteosarcoma cells [ 162 , 163 ] ② Ferroptosis inducers in other cells BAY 11–7085 NFKBIA/IkBa inhibitor, HMOX1 overexpression Fe 2+ ↑, GPX4 ↓, ROS ↑, MDA ↑ MDA-MB-231, MCF-7, MDA-MB-468, SKBR3 [ 164 ] BAY 87–2243 Mitochondrial complex I inhibitor Mitochondrial membrane potential ↓, ROS ↑ G361, SK-MEL-28 [ 165 ] Cyst(e)inase Cyst(e)ine consumption ...…”

Section: Progress Of Research On Ferroptosis In Sarcoma Treatmentmentioning

confidence: 99%

“…It not only upregulates HMOX1 protein expression but also significantly reduces the levels of the antioxidant CoQ10. Additionally, zoledronic acid increases the expression of POR, an enzyme required for lipid peroxidation [ 162 , 163 ]. These combined actions enhance the propensity for ferroptosis in osteosarcoma cells.…”

Section: Progress Of Research On Ferroptosis In Sarcoma Treatmentmentioning

confidence: 99%

Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects

Zeng,

Zhang,

Lin

et al. 2024

Exp Hematol Oncol

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Sarcoma is a malignant tumor that originates from mesenchymal tissue. The common treatment for sarcoma is surgery supplemented with radiotherapy and chemotherapy. However, patients have a 5-year survival rate of only approximately 60%, and sarcoma cells are highly resistant to chemotherapy. Ferroptosis is an iron-dependent nonapoptotic type of regulated programmed cell death that is closely related to the pathophysiological processes underlying tumorigenesis, neurological diseases and other conditions. Moreover, ferroptosis is mediated via multiple regulatory pathways that may be targets for disease therapy. Recent studies have shown that the induction of ferroptosis is an effective way to kill sarcoma cells and reduce their resistance to chemotherapeutic drugs. Moreover, ferroptosis-related genes are related to the immune system, and their expression can be used to predict sarcoma prognosis. In this review, we describe the molecular mechanism underlying ferroptosis in detail, systematically summarize recent research progress with respect to ferroptosis application as a sarcoma treatment in various contexts, and point out gaps in the theoretical research on ferroptosis, challenges to its clinical application, potential resolutions of these challenges to promote ferroptosis as an efficient, reliable and novel method of clinical sarcoma treatment.

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“…It acts as an antioxidant enzyme and conveys an antiapoptotic effect through the p38 MAPK pathway, the NF-κB/PI3K/AKT pathway, and others [214,215]. It is found to be increased in patients with OS [216] and an increased expression in OS cells protects them from ferroptosis and chemotherapy [217]. The inhibition of HMOX-1 causes iron accumulation and the formation of ROS and LOOH [218].…”

Section: Redox Sensitive Signaling In Os 431 Keap1/nrf2 Signaling Pat...mentioning

confidence: 99%

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma

Borović Šunjić,

Jaganjac,

Vlainić

et al. 2024

IJMS

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Oxidative stress and lipid peroxidation play important roles in numerous physiological and pathological processes, while the bioactive products of lipid peroxidation, lipid hydroperoxides and reactive aldehydes, act as important mediators of redox signaling in normal and malignant cells. Many types of cancer, including osteosarcoma, express altered redox signaling pathways. Such redox signaling pathways protect cancer cells from the cytotoxic effects of oxidative stress, thus supporting malignant transformation, and eventually from cytotoxic anticancer therapies associated with oxidative stress. In this review, we aim to explore the status of lipid peroxidation in osteosarcoma and highlight the involvement of lipid peroxidation products in redox signaling pathways, including the involvement of lipid peroxidation in osteosarcoma therapies.

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Zoledronic acid induces ferroptosis by reducing ubiquinone and promoting HMOX1 expression in osteosarcoma cells

Cited by 11 publications

References 44 publications

Ferroptosis-related gene HIC1 in the prediction of the prognosis and immunotherapeutic efficacy with immunological activity

Ferroptosis-related gene HIC1 in the prediction of the prognosis and immunotherapeutic efficacy with immunological activity

Harnessing ferroptosis for enhanced sarcoma treatment: mechanisms, progress and prospects

Lipid Peroxidation-Related Redox Signaling in Osteosarcoma

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