Hypoxia-induced HIF-1α/lncRNA-PMAN inhibits ferroptosis by promoting the cytoplasmic translocation of ELAVL1 in peritoneal dissemination from gastric cancer

Lin, Zaihuan; Song, Jialin; Gao, Yuke; Huang, Sihao; Dou, Rongzhang; Zhong, Panyi; Huang, Guoquan; Han, Lei; Zheng, Jinsen; Zhang, Xinyao; Wang, Shuyi; Xiong, Bin

doi:10.1016/j.redox.2022.102312

Cited by 107 publications

(83 citation statements)

References 47 publications

(59 reference statements)

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“…However, HIF-2 signaling was also reported to reduce oxidative stress by inducing the transcription of nucleoside diphosphate-linked moiety X-type motif 1 in clear cell renal cell carcinoma, which promoted tumor growth [53]. HIF-1α, on the other hand, was attributed a protective effect against ferroptosis in several cancer cells by reducing iron and ROS levels [54], promoting lipid storage and regulating lipid metabolism [55][56][57]. In line with previous observations, high expression of the HIF-1 target gene carbonic anhydrase 9 had protective effects against ferroptosis in a model of malignant mesothelioma [58].…”

Section: Discussionmentioning

confidence: 99%

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

Henning

Blind²,

Larafa³

et al. 2022

Cell Death Dis

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Oxidative stress and hypoxia in the retinal pigment epithelium (RPE) have long been considered major risk factors in the pathophysiology of age-related macular degeneration (AMD), but systematic investigation of the interplay between these two risk factors was lacking. For this purpose, we treated a human RPE cell line (ARPE-19) with sodium iodate (SI), an oxidative stress agent, together with dimethyloxalylglycine (DMOG) which leads to stabilization of hypoxia-inducible factors (HIFs), key regulators of cellular adaptation to hypoxic conditions. We found that HIF stabilization aggravated oxidative stress-induced cell death by SI and iron-dependent ferroptosis was identified as the main cell death mechanism. Ferroptotic cell death depends on the Fenton reaction where H2O2 and iron react to generate hydroxyl radicals which trigger lipid peroxidation. Our findings clearly provide evidence for superoxide dismutase (SOD) driven H2O2 production fostering the Fenton reaction as indicated by triggered SOD activity upon DMOG + SI treatment as well as by reduced cell death levels upon SOD2 knockdown. In addition, iron transporters involved in non-transferrin-bound Fe2+ import as well as intracellular iron levels were also upregulated. Consequently, chelation of Fe2+ by 2’2-Bipyridyl completely rescued cells. Taken together, we show for the first time that HIF stabilization under oxidative stress conditions aggravates ferroptotic cell death in RPE cells. Thus, our study provides a novel link between hypoxia, oxidative stress and iron metabolism in AMD pathophysiology. Since iron accumulation and altered iron metabolism are characteristic features of AMD retinas and RPE cells, our cell culture model is suitable for high-throughput screening of new treatment approaches against AMD.

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Section: Discussionmentioning

confidence: 99%

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

Henning

Blind²,

Larafa³

et al. 2022

Cell Death Dis

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“…Lnc-PMAN Translocates ELAVL1 from the nucleus to the cytoplasm, and cytoplasmic ELAVL1 increases the stability of SLC7A11 mRNA. High cytoplasmic expression of SLC7A11 increases GSH expression and decreases ROS levels, thereby inhibiting ferroptosis [ 91 ]. Another study showed that DpdtbA induced ferroptosis in gastric cancer cells by activating the P53 and PHD2/HIF-1α signaling pathways in gastric cancer [ 92 ].…”

Section: Regulation Of Cell Death In Gastric Cancermentioning

confidence: 99%

“…Table 1 shows several non-coding RNAs that regulate programmed cell death in gastric cancer cells [ 91 , 95 – 98 ]. The low expression of lncRNA SNHG1 in gastric cancer leads to the upregulation of miR-21-5p expression to suppress the level of downstream TLR4, thereby inhibiting the activation of intracellular necroptosis [ 95 ].…”

Section: Regulation Of Cell Death In Gastric Cancermentioning

confidence: 99%

“…High expression of ADAMTS9-AS2 enhanced the sensitivity to cisplatin, which was mainly due to ADAMTS9-AS2 sponging miR-223-3p to promote the expression of NLRP3, thus promoting pyroptosis in gastric cancer cells [ 96 ]. Hypoxia-induced lncRNA-PMAN increases the stability of SLC7A11 by facilitating the translocation of ELAVL1 from the nucleus to the cytoplasm, thereby inhibiting ferroptosis in gastric cancer cells [ 91 ]. The lncRNA BDNF-AS is highly expressed in gastric cancer and affects the ubiquitination of VDAC3 via WDR5/FBXW7, thereby inhibiting ROS accumulation and ferroptosis in cells [ 97 ].…”

Section: Regulation Of Cell Death In Gastric Cancermentioning

confidence: 99%

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Cell death affecting the progression of gastric cancer

et al. 2022

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Gastric cancer is a gastrointestinal tumor with high morbidity and mortality rates. Several factors influence its progression, cell death being an important element. In this review, we summarized the effects of necrosis, apoptosis, necroptosis, pyroptosis, ferroptosis, and eight less common cell death modalities on gastric cancer cells and the tumor microenvironment, detailed the molecular mechanisms of various cell death and their major regulatory pathways in gastric cancer, explored the prevalence and complexity of cell death in gastric cancer progression and highlighted the potentials of cell death-related therapies in gastric cancer.

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“…Everolimus and RSL3/erastin show cooperative antiproliferation and ferroptosis in renal cancer cells by suppressing mTOR-4EBP1 signaling [ 306 ]. Hypoxia-induced HIF1A suppresses ferroptosis in metastasis of gastric cancer [ 318 ]. GSK-3β is a positive effector of ferroptosis.…”

Section: Akt Effectors Modulate Cell Functionsmentioning

confidence: 99%

The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products

et al. 2022

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Oxidative stress and AKT serine-threonine kinase (AKT) are responsible for regulating several cell functions of cancer cells. Several natural products modulate both oxidative stress and AKT for anticancer effects. However, the impact of natural product-modulating oxidative stress and AKT on cell functions lacks systemic understanding. Notably, the contribution of regulating cell functions by AKT downstream effectors is not yet well integrated. This review explores the role of oxidative stress and AKT pathway (AKT/AKT effectors) on ten cell functions, including apoptosis, autophagy, endoplasmic reticulum stress, mitochondrial morphogenesis, ferroptosis, necroptosis, DNA damage response, senescence, migration, and cell-cycle progression. The impact of oxidative stress and AKT are connected to these cell functions through cell function mediators. Moreover, the AKT effectors related to cell functions are integrated. Based on this rationale, natural products with the modulating abilities for oxidative stress and AKT pathway exhibit the potential to regulate these cell functions, but some were rarely reported, particularly for AKT effectors. This review sheds light on understanding the roles of oxidative stress and AKT pathway in regulating cell functions, providing future directions for natural products in cancer treatment.

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Hypoxia-induced HIF-1α/lncRNA-PMAN inhibits ferroptosis by promoting the cytoplasmic translocation of ELAVL1 in peritoneal dissemination from gastric cancer

Cited by 107 publications

References 47 publications

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

Hypoxia aggravates ferroptosis in RPE cells by promoting the Fenton reaction

Cell death affecting the progression of gastric cancer

The Impact of Oxidative Stress and AKT Pathway on Cancer Cell Functions and Its Application to Natural Products

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