FSP1-mediated ferroptosis in cancer: from mechanisms to therapeutic applications.

Ferroptosis is a new discovered regulated cell death triggered by the ferrous ion (Fe2+)-dependent accumulation of lipid peroxides associated with cancer and many other diseases. The mechanism of ferroptosis includes oxidation systems (such as enzymatic oxidation and free radical oxidation) and antioxidant systems (such as GSH/GPX4, CoQ10/FSP1, BH4/GCH1 and VKORC1L1/VK). Among them, ferroptosis suppressor protein 1 (FSP1), as a crucial regulatory factor in the antioxidant system, has shown a crucial role in ferroptosis. FSP1 has been well validated to ferroptosis in three ways, and a variety of intracellular factors and drug molecules can alleviate ferroptosis via FSP1, which has been demonstrated to alter the sensitivity and effectiveness of cancer therapies, including chemotherapy, radiotherapy, targeted therapy and immunotherapy. This review aims to provide important frameworks that, bring the regulation of FSP1 mediated ferroptosis into cancer therapies on the basis of existing studies.

Regulators of epigenetic change in ferroptosis­associated cancer (Review).

The occurrence of tumors is associated with the upregulation or downregulation of certain genes. The identification of novel tumor therapies has revealed that regulation of tumor cell death can either promote or suppress the occurrence and development of tumors. Iron­dependent lipid free oxygen radical accumulation causes tumor cells to die by ferroptosis, a form of regulated cell death. Multiple mechanisms mediate this mode of cell death, including redox homeostasis, iron metabolism, mitochondrial activity, breakdown of amino acids, lipids and sugars and epigenetic regulatory and disease­associated signaling pathways. The present review discussed epigenetic mechanism of ferroptosis with the aim of providing novel insight for optimization of the effects of antitumor therapy.

COUP-TFII promotes metastasis and epithelial-to-mesenchymal transition through upregulating Snail in human intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) arises from cholangiocytes in the intrahepatic bile duct and is the second most common type of liver cancer. The overexpression of COUP-TFII has been observed in several types of malignancies. However, its role in ICC progression remains unclear. In this study, we found that the protein level of COUP-TFII was increased, but the mRNA level was unchanged in ICC tissues. High protein expression was positively associated with tumor size, lymph node metastasis, and poor prognosis in ICC patients. Furthermore, the overexpression of COUP-TFII promoted the proliferation, migration, and invasion of ICC cells in vitro and enhanced tumor growth and metastasis in nude mouse models. Mechanistic studies revealed that COUP-TFII induced epithelial-to-mesenchymal transition in ICC cells by upregulating Snail expression. Moreover, the activation of PI3K/AKT signaling led to the upregulation of COUP-TFII protein expression in ICC. Together, these findings indicate that COUP-TFII promotes epithelial-to-mesenchymal transition and metastasis in ICC and suggest that this protein is a potential target for adjuvant therapy for these patients.

Dihydromethysticin, a natural molecule from Kava, suppresses the growth of colorectal cancer via the NLRC3/PI3K pathway.

Dihydromethysticin (DHM), a natural compound derived from Kava, has been reported to be effective against mental disorders and some malignant tumors. However, little is known about the inhibitory effect of DHM on colorectal cancer (CRC). First, we examined the impact of DHM on human colon cancer cell lines, which demonstrated that DHM inhibits proliferation, migration, and invasion and promotes apoptosis and cell cycle arrest in colon cancer cells in vitro. Using small hairpin RNA, we inhibited nucleotide-oligomerization domain-like receptor subfamily C3 (NLRC3)/phosphoinositide 3-kinase (PI3K) pathway to elucidate the partial signaling of DHM-mediated tumor suppression. Additionally, using an ectopic human CRC model, we verified whether DHM inhibits tumor growth and angiogenesis via the NLRC3/PI3K pathway in vivo. Overall, DHM showed an inhibitory effect on CRC by altering cell proliferation, migration, invasion, apoptosis, cell cycle, and angiogenesis, possibly via the NLRC3/PI3K pathway. Thus, DHM may be a promising candidate for CRC therapy.

Overexpressed lncRNA GATA6-AS1 Inhibits LNM and EMT via FZD4 through the Wnt/ß-Catenin Signaling Pathway in GC.

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide. Accumulating evidence reveals the significance of long non-coding RNAs (lncRNAs) in various cancers. The current study aimed to evaluate the role of GATA6 antisense RNA 1 (GATA6-AS1) in the epithelial-mesenchymal transition (EMT) and lymph node metastasis (LNM) in GC. GC-related microarray datasets were initially retrieved from the GEO with differentially expressed lncRNAs screened, followed by evaluation of the regulatory relationship between Frizzled 4 (FZD4) and GATA6-AS1. The detailed regulatory mechanism by which GATA6-AS1 influences the Wnt/ß-catenin signaling pathway and GC cell biological behaviors was investigated by treating SGC7901 cells with overexpressed GATA6-AS1, specific antisense oligonucleotide against GATA6-AS1, and lithium chloride (LiCl; activator of the Wnt/ß-catenin signaling pathway). Finally, xenograft nude mice were used to assay tumor growth and LNM in vivo. GATA6-AS1 was poorly expressed, but FZD4 was highly expressed in GC tissues and cells. Elevated GATA6-AS1 reduced FZD4 expression by recruiting enhancer of zeste homolog 2 (EZH2) and trimethylation at lysine 27 of histone H3 (H3K27me3) to the FZD4 promoter region via the inactivated Wnt/ß-catenin signaling pathway, whereby cell invasion, migration, and proliferation, tumor growth, and LNM in nude mice were reduced. Taken together, overexpressed GATA6-AS1 downregulated the expression of FZD4 to inactivate the Wnt/ß-catenin signaling pathway, which ultimately inhibited GC progression.

(-)-Oleocanthal inhibits growth and metastasis by blocking activation of STAT3 in human hepatocellular carcinoma.

We explored the anti-cancer capacity of (-)-oleocanthal in human hepatocellular carcinoma (HCC). (-)-Oleocanthal inhibited proliferation and cell cycle progression and induced apoptosis in HCC cells in vitro and suppressed tumor growth in an orthotopic HCC model. (-)-Oleocanthal also inhibited HCC cell migration and invasion in vitro and impeded HCC metastasis in an in vivo lung metastasis model. ( )-Oleocanthal acted by inhibiting epithelial-mesenchymal transition (EMT) through downregulation Twist, which is a direct target of STAT3. (-)-Oleocanthal also reduced STAT3 nuclear translocation and DNA binding activity, ultimately downregulating its downstream effectors, including the cell cycle protein Cyclin D1, the anti-apoptotic proteins Bcl-2 and survivin, and the invasion-related protein MMP 2. Overexpression of constitutively active STAT3 partly reversed the anti cancer effects of (-)-oleocanthal, which inhibited STAT3 activation by decreasing the activities of JAK1 and JAK2 and increasing the activity of SHP-1. These data suggest that (-)-oleocanthal may be a promising candidate for HCC treatment.

Matrine inhibits breast cancer growth via miR-21/PTEN/Akt pathway in MCF-7 cells.

BACKGROUND: Matrine is one of the major alkaloids extracted from Sophora flavescens and has been used clinically for breast cancer with notable therapeutic efficacy in China. However, the mechanisms are still largely unknown. METHODS: Cell viability was analyzed by MTT assay. After MCF-7 cells were treated with matrine for 48h, apoptosis was detected by flow cytometry, TUNEL assay and transmission electron microscopy, and the cell cycle distribution was also analyzed by flow cytometry. Further, the expression of PTEN, pAkt, Akt, pBad, Bad, p21(/WAF1/CIP1), and p27(/KIP1) was determined by Western blot. Changes of miR-21 level were quantified by real-time RT-PCR. After miR-21 was transfected in MCF-7 cells, PTEN protein level was measured by Western blot. RESULTS: Matrine inhibited MCF-7 cell growth in a concentration-and time-dependent manner, by inducing apoptosis and cell cycle arrest at G(1)/S phase. Matrine up-regulated PTEN by downregulating miR-21 which in turn dephosphorylated Akt, resulting in accumulation of Bad, p21(/WAF1/CIP1) and p27(/KIP1). CONCLUSION: Our study unraveled, for the first time, the ability of matrine to suppress breast cancer growth and elucidated the miR-21/PTEN/Akt pathway as a signaling mechanism for the anti-cancer action of matrine. Our findings also reinforce the notion that miRNAs can act as mediators of the therapeutic efficacy of natural medicines.

The role of AKT1 and autophagy in the protective effect of hydrogen sulphide against hepatic ischemia/reperfusion injury in mice.

Hydrogen sulphide (H 2S) exerts a protective effect in hepatic ischemia-reperfusion (I/R) injury. However, the exact mechanism of H 2S action remains largely unknown. This study was designed to investigate the role of the PtdIns3K-AKT1 pathways and autophagy in the protective effect of H 2S against hepatic I/R injury. Primary cultured mouse hepatocytes and livers with or without NaHS (a donor of H 2S) preconditioning were exposed to anoxia/reoxygenation (A/R) and I/R, respectively. In certain groups, they were also pretreated with LY294002 (AKT1-specific inhibitor), 3-methyladenine (3MA, autophagy inhibitor) or rapamycin (autophagy enhancer), alone or simultaneously. Cell viability, expression of P-AKT1, T-AKT1, LC3 and BECN1 were examined. The severity of liver injury was measured by the levels of serum aminotransferase and inflammatory cytokine, apoptosis and histological examination. GFP-LC3 redistribution and transmission electron microscopy were used to test the activity of autophagy. H 2S preconditioning activated PtdIns3K-AKT1 signaling in hepatocytes. LY294002 could abolish the AKT1 activation and attenuate the protective effect of H 2S on hepatocytes A/R and hepatic I/R injuries. H 2S suppressed hepatic autophagy in vitro and in vivo. Further reducing autophagy by 3MA also diminished the protective effect of H 2S, while rapamycin could reverse the autophagy inhibitory effect and enhance the protective effect of H 2S against hepatocytes A/R and hepatic I/R injuries, consequently. Taken together, H 2S protects against hepatocytic A/R and hepatic I/R injuries, at least in part, through AKT1 activation but not autophagy. An autophagy agonist could be applied to potentiate this hepatoprotective effect by reversing the autophagy inhibition of H 2S.

S-allylmercaptocysteine effectively inhibits the proliferation of colorectal cancer cells under in vitro and in vivo conditions.

S-allylmercaptocysteine (SAMC), one of the water-soluble organosulfur garlic derivatives, has been demonstrated as a suppressive agent against some tumors. The effects of SAMC on the proliferation and metastasis of colorectal cancer (CRC) under in vitro and in vivo conditions were evaluated here. The viabilities and migrations of CRC cells SW480, SW620, Caco-2 treated with SAMC were measured by MTT, scratch-wound, and transwell assays. The in vivo anticancer effect of SAMC against luciferase-expressing SW620 xenografts in mice was determined by bioluminescence imaging and histopathology observation. The apoptosis of SAMC-treated CRC cells was examined by Western blotting. The results demonstrate that SAMC could effectively suppress the growth and metastasis of colorectal cancer cells both in vivo and in vitro. The anticancer effect of SAMC was related to the decreased proliferation and increased apoptosis as well as necrosis of cancer cells. Oral administration of SAMC in the quantity/concentration used had no apparent toxic side effect on the vital organs of the experimental mice. Taken together, the proliferation and metastasis of CRC cells can be significantly suppressed by SAMC treatment under both in vitro and in vivo conditions. SAMC may thus be a promising candidate for CRC chemotherapy.