The regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy.

Ferroptosis is an iron-dependent programmed cell death process that involves lipid oxidation via the Fenton reaction to produce lipid peroxides, causing disruption of the lipid bilayer, which is essential for cellular survival. Ferroptosis has been implicated in the occurrence and treatment response of various types of cancer, and targeting ferroptosis has emerged as a promising strategy for cancer therapy. However, cancer cells can escape cellular ferroptosis by activating or remodeling various signaling pathways, including oxidative stress pathways, thereby limiting the efficacy of ferroptosis-activating targeted therapy. The key anti-oxidative transcription factor, nuclear factor E2 related factor 2 (Nrf2 or NFE2L2), plays a dominant role in defense machinery by reprogramming the iron, intermediate, and glutathione peroxidase 4 (GPX4)-related network and the antioxidant system to attenuate ferroptosis. In this review, we summarize the recent advances in the regulation and function of Nrf2 signaling in ferroptosis-activated cancer therapy and explore the prospect of combining Nrf2 inhibitors and ferroptosis inducers as a promising cancer treatment strategy.

G protein coupled receptor kinase 5 modifies the nucleolar stress response activated by actinomycin D.

G protein coupled receptor kinase 5 (GRK5) is localized within the nucleus and moderates functions such as DNA transcription, in addition to its localization at the plasma membrane. In this report, we show that GRK5 modifies the nucleolar stress response activated by the DNA polymerase inhibitor, actinomycin D (ActD). We show an increased sensitivity to the apoptotic effects of ActD on cervical HeLa cells and the breast cancer cell line MDA MB 231 with reduced protein expression of GRK5. We also tested two types of breast cancer cells (MDA MB 231 and MCF7 cells) and found that the rate of response to ActD varied between them because they have innate differences in the protein expression of GRK5. We also found that GRK5 phosphorylates nucleophosmin (NPM1) at T199 before and during the early stages of ActD treatment. Phosphorylation at T199 increases the ability of NPM1 to interact with p14ARF in vitro, which may affect the protein expression levels of p14ARF. We found that the expression levels of p14ARF were lower in the cells transfected with the control shRNA, but higher in cells transfected with GRK5 shRNA. Collectively, this suggests that GRK5 modifies the nucleolar stress response associated with ActD.

SOAT1 is a new prognostic factor of colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant gastrointestinal cancers. Metastasis is the major leading cause of death in patients with CRC, and many patients treated with radical surgery were diagnosed with metastasis during follow-up. However, the underlying molecular mechanisms regulating CRC metastasis are still elusive. Sterol o-acyltransferase 1 (SOAT1) is a critical participant in maintaining intracellular cholesterol balance. Here, by analyzing the clinical specimens and in vitro cell line experiments, we evaluated the clinical relevance and role of SOAT1 in regulating CRC metastasis. The results revealed that SOAT1 was overexpressed in colon cancer tissues compared to peritumor tissues at mRNA and protein levels. High intratumor SOAT1 expression correlates to lymph node metastasis and indicates poor patient disease-free survival and overall survival. The silencing of SOAT1 strongly inhibited the migration and invasion ability of CRC tumor cells. These results demonstrated that SOAT1 was upregulated in colon cancer. Upregulation of SOAT1 expression may promote CRC progression by enhancing the migration and invasion ability of CRC. Our results indicate that targeting SOAT1 activity may be applied as a promising therapeutic strategy for preventing the metastasis of CRC after radical surgical treatment.

IGF-1C domain-modified hydrogel enhanced the efficacy of stem cells in the treatment of AMI.

BACKGROUND: Due to the low survival rate of cell transplantation, stem cell has not been widely used in clinical treatment of acute myocardial infarction (AMI). In this study, we immobilized the C domain peptide of insulin-like growth factor-1 on chitosan (CS-IGF-1C) to obtain bioactive hydrogel. The purpose was to investigate whether CS-IGF-1C hydrogel incorporated with human placenta-derived mesenchymal stem cells (hP-MSCs) can boost the survival of hP-MSCs and enhance their therapeutic effects. METHODS: hP-MSCs, which continuously expressed green fluorescent protein (GFP) and firefly luciferase (Fluc), were transplanted with CS-IGF-1C hydrogel into a mouse myocardial infarction model. Cell survival was detected by bioluminescence imaging (BLI), and cardiac function was measured by echocardiogram. Real-time PCR and histological analysis were used to explore the therapeutic mechanism of CS-IGF-1C hydrogel. RESULTS: CS-IGF-1C hydrogel could induce the proliferation of hP-MSCs and exert anti-apoptotic effects in vitro. The Calcine-AM/PI staining results showed that hP-MSCs seeded on CS-IGF-1C hydrogel could protect neonatal mouse ventricular cardiomyocytes (NMVCs) against oxidative stress. It was observed by BLI that CS-IGF-1C hydrogel injected into ischemic myocardium could improve the survival rate of hP-MSCs. Histology analysis indicated that co-transplantation of the CS-IGF-1C hydrogel and hP-MSCs could increase angiogenesis, reduce collagen deposition, ameliorate left ventricular expanded, and further promote the recovery of cardiac function. Besides, we found that the inflammatory response was inhibited and the expression of apoptosis-related genes was downregulated by CS-IGF-1C hydrogel. CONCLUSIONS: CS-IGF-1C hydrogel provides a conducive microenvironment for cells and significantly boosts the survival of hP-MSCs in mouse myocardial infarction model, which suggest that it may be a potential candidate for prolonging the therapeutic effect of hP-MSCs during AMI.

Correction to: IGF-1C domain-modified hydrogel enhanced the efficacy of stem cells in the treatment of AMI.

An amendment to this paper has been published and can be accessed via the original article.