Dataset Information

Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway.

ABSTRACT: Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma.

SUBMITTER: Liu CC

PROVIDER: S-EPMC8773805 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway.

Liu Chen-Chi CC Li Hsin-Hsien HH Lin Jiun-Han JH Chiang Ming-Chen MC Hsu Tien-Wei TW Li Anna Fen-Yau AF Yen David Hung-Tsang DH Hsu Han-Shui HS Hung Shih-Chieh SC

Biomolecules 20211229 1

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exp ...[more]

PMID: 35053196

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Project description:BackgroundIntestinal ischemia-reperfusion injury occurs in acute intestinal obstruction, intussusception, acute mesenteric artery embolism, and other diseases and can lead to local intestinal necrosis, distant organ involvement, or systemic reactions, with high morbidity and mortality. Ferroptosis plays a crucial role in intestinal ischemia-reperfusion injury, and inhibition of ferroptosis may provide new approaches for treating the disease. SIRT3 protects cells from oxidative stress and may be involved in the process of ferroptosis. We hypothesized that resveratrol, an agonist of SIRT3, could ameliorate intestinal ischemia-reperfusion injury by compensating the GSH/GPX4 pathway.MethodsIntestinal ischemia-reperfusion (I/R) and Caco-2 hypoxia-reoxygenation models were established. Transmission electron microscopy was used to assess mitochondrial function; the Chiu's score was used to evaluate the degree of intestinal mucosal injury based on HE staining; and Western blot was used to detect the SIRT3/FoxO3a pathway, tight junction proteins and ferroptosis-related protein expression. Sirt3-/- C57, shSIRT3-Caco-2 cells and siFoxO3a-Caco-2 cells were established. C11-BODIPY was used to detect lipid peroxide in cells; FD4 and IFABP were used to detect intestinal permeability; MitoSOX was used to detect ROS levels; and MitoTracker and immunofluorescence colocalization were used to detect SIRT3 levels.ResultsIn the intestinal I/R model, I/R injury occurs mainly during the reperfusion period and leads to ferroptosis through the GSH/GPX4 pathway. Resveratrol could reduce ferroptosis and ameliorate I/R injury by activating SIRT3. In Sirt3-/- mice, more intestinal mucosal cells underwent ferroptosis, I/R injury was more severe, and resveratrol lost the ability to ameliorate I/R injury. In addition, hypoxia-reoxygenation increased RSL3-induced ferroptosis sensitivity in Caco-2 cells in vitro. In the presence of shSIRT3 or RSL3 alone, resveratrol could ameliorate Caco-2 ferroptosis, but not RSL3-induced shSIRT3-Caco-2 ferroptosis. Furthermore, resveratrol might activate the SIRT3/FoxO3a pathway, increase the expression of SOD2 and catalase, and inhibit ROS generation, thus reducing lipid peroxidation and ferroptosis.ConclusionTo date, this is the first study to show that resveratrol ameliorates intestinal ischemia-reperfusion injury by activating SIRT3 and reducing ferroptosis. Resveratrol can reduce intestinal ischemia-reperfusion injury by activating the SIRT3/FoxO3a pathway, increasing the expression of SOD2 and catalase, reducing ROS and LPO production, compensating for the GSH/GPX4 pathway and inhibiting ferroptosis. Resveratrol increases the expression of SOD2 and catalase, reduces the production of ROS and LPO, compensates for the GSH/GPX4 pathway and inhibits ferroptosis by activating the SIRT3/FoxO3a pathway.

Project description:Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.

Dataset Information

Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway.

Publications

Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway.

Similar Datasets

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