Background/Aims: As a very common malignancy of the digestive system, the incidence and mortality rates of gastric cancer (GC) are increasing year by year. The critical role of ferroptosis in cancer development has been well-documented. The polyphenol compound curcumin shows prominent anti-tumor effects in multiple cancer types, including GC. However, whether curcumin participates in GC tumorigenesis by regulating ferroptosis remains unknown. Materials and Methods: Gastric cancer cells AGS and HGC-27 were treated with curcumin (0, 10, and 20 μM). Cell viability and death were evaluated through CCK-8 and LDH release assays. LC3B expression in cells was estimated through immunofluorescence staining. Intracellular ferrous iron (Fe2+), GSH, MDA, and lipid ROS levels were assessed by corresponding assay kits. The cellular levels of autophagy markers (ATG5, ATG7, Beclin 1, and LC3B), ferroptosis markers (ACSL4, SLC7A11, and GPX4), and phosphorylated (p)-PI3K, p-AKT, and p-mTOR were determined through western blotting. Results: Curcumin attenuated cell viability but stimulated cell death in GC cells. Curcumin enhanced autophagy in GC cells, as demonstrated by the increased levels of ATG5, ATG7, Beclin 1, and LC3B. Besides, curcumin upregulated iron, MDA, GSH, and ACSL4 levels while downregulated lipid ROS, SLC7A11, and GPX4 levels, suggesting its stimulation on ferroptosis in GC cells. Curcumin decreased p-PI3K, p-AKT, and p-mTOR levels in cells. Importantly, the ferroptosis inhibitor ferrostatin-1 overturned the impacts of curcumin on GC cell viability, death, and ferroptosis. Conclusion: Curcumin suppresses GC development by inducing autophagy-mediated ferroptosis by inactivating the PI3K/AKT/mTOR signaling. Cite this article as: Zheng X, Liu J, Hu W, et al. Curcumin induces autophagy-mediated ferroptosis by targeting the PI3K/AKT/mTOR signaling pathway in gastric cancer. Turk J Gastroenterol. 2024;35(8):625-633.

The aim of this study was to investigate the role of tumor-associated neutrophils (TANs) in the metastasis of pancreatic ductal adenocarcinoma (PDAC), to explore the regulation of TANs, and to determine the mechanisms governing the metastasis of PDAC. The correlation between neutrophils and the patient’s clinical pathological data was first evaluated. Then, the effects of neutrophils on the invasion of PDAC were analyzed using a combination of conditioned media, direct and indirect coculture of human peripheral blood neutrophils, and PDAC cell lines (Panc-1, MiaPaCa-2 and AsPC-1). The cytokines secreted by neutrophils were detected through ELISA. TAN density was significantly correlated with poor metastasis-free survival (P < .05). Through coculture, it was found that the effect of neutrophils on pancreatic cancer cells was dependent on concentration, and a high concentration of neutrophils showed a lethal effect, while a low concentration of neutrophils primarily promoted the migration ability of cancer cells. The results of the wound-healing assay, the Transwell invasion assay, and laser confocal microscopy confirmed the promoting effect and indicated that the effect of neutrophils toward cancer cells may function indirectly by releasing a series of cytokines. The results of ELISA show that this effect may be achieved through the secretion of a large amount of TNF-α and TGF-β1 by neutrophils. Our study indicated that neutrophils may increase the metastasis of PDAC by releasing a series of cell cytokines, such as TNF-α and TGF-β1.

Colorectal cancer (CRC) is one of the most common cancers and the second most deadly cancer across the globe. Colorectal cancer stem cells (CCSCs) fuel CRC growth, metastasis, relapse, and chemoresistance. A complete understanding of the modulatory mechanisms of CCSC biology is essential for developing efficacious CRC treatment. In the current study, we characterized the expression and function of GTP binding protein 2 (GTPBP2) in a chemical-induced mouse CRC model. We found that GTPBP2 was expressed at a higher level in CD133⁺CD44⁺ CCSCs compared with other CRC cells. Using a lentivirus-based Cas9/sgRNA system, GTPBP2 expression was ablated in CRC cells in vitro. GTPBP2 deficiency caused the following effects on CCSCs: 1) Significantly accelerating proliferation and increasing the proportions of cells at G1, S, and G2/M phase; 2) Impairing resistance to 5-Fluorouracil; 3) Weakening self-renewal but not impacting cell migration. In addition, GTPBP2 deficiency remarkably decreased β-catenin expression while increasing β-catenin phosphorylation in CCSCs. These effects of GTPBP2 were present in CCSCs but not in other CRC cell populations. The Wnt agonist SKL2001 completely abolished these changes in GTPBP2-deficient CCSCs. When GTPBP2-deficient CCSCs were implanted in nude mice, they exhibited consistent changes compared with GTPBP2-expressing CCSCs. Collectively, this study indicates that GTPBP2 positively modulates Wnt signaling to reinforce the quiescence, self-renewal, and chemoresistance of mouse CCSCs. Therefore, we disclose a novel mechanism underlying CCSC biology and GTPBP2 could be a therapeutic target in future CRC treatment.

Natural killer (NK) cells constitute an active and potent anti-tumor effector population against multiple malignancies. NK cells exploit tumoricidal machinery to restrain colorectal carcinoma (CRC) expansion and invasion. Nonetheless, it is becoming increasingly evident that functional exhaustion considerably compromises the potency of NK cells in patients with CRC. To elucidate the factors that impair NK cell function in the context of CRC, we determined the role of zinc finger protein 335 (ZFP335) in modulating NK cell activity in mouse CRC induced by azoxymethane and dextran sulfate sodium. ZFP335 was profoundly decreased in NK cells in mesenteric lymph nodes of CRC-bearing mice. ZFP335 was especially diminished in NK cells that were both phenotypically and functionally exhausted. Besides, effective ZFP335 knockdown markedly undermined NK cell proliferation, tumoricidal protein production, degranulation, and cytotoxic efficacy on malignant cells, strongly suggesting that ZFP335 reinforces NK cell function. Importantly, ZFP335 knockdown lowered the expression of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), both of which play crucial roles in NK cell homeostasis and activation. Collectively, ZFP335 down-regulation is essential for NK cell exhaustion in mesenteric lymph nodes of mice with CRC. We discovered a new ZFP335-JAK1/3 signaling pathway that modulates NK cell exhaustion.