Cancer-associated fibroblast-derived circFARP1 modulates non-small cell lung cancer invasion and metastasis through the circFARP1/miR-338-3p/SOX4 axis.

The pleiotropic effect of cancer-associated fibroblasts (CAFs) on tumour progression depends on the environment. circFARP1 is critical for CAFs-induced gemcitabine (GEM) resistance in pancreatic cancer. Its specific role and mechanism in non-small cell lung cancer (NSCLC) have not been reported yet. We prepared a cancer-associated fibroblasts-conditioned medium (CAF-CM) to incubate the A549 cells. Quantitative real-time polymerase chain reaction was used to detect RNA levels. We detected protein expression by immunohistochemistry, immunocytochemistry, western blot and immunofluorescence. We also detected the targeting impact between circFARP1, miR-338-3p and SRY-box transcription factor 4 (SOX4) by using dual-luciferase reporter and RNA pull-down assays. We determined cell proliferation, migration and invasion capabilities through Cell Counting Kit-8 and transwell assays. In addition, we measured tumour volume and weight in vivo by establishing a xenograft tumour model. CircFARP1 levels were remarkably high in the CAFs. The transfection experiments found that circFARP1 downregulation in CAFs caused migration, proliferation and invasion inhibition of CAFs and A549 cells, whereas inhibiting miR-38-3p or overexpressing SOX4 in CAFs could significantly reverse the inhibition. In vivo study in nude mice confirmed that CAFs could promote NSCLC tumour growth and knockdown of circFARP1 could inhibit tumour growth of NSCLC, whereas miR-38-3p downregulation or SOX4 overexpression could significantly reverse the inhibition. circFARP1 promotes NSCLC development by stimulating miR-338-3p/SOX4 signalling axis to regulate CAFs.

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases.

Ferroptosis, a unique modality of cell death with mechanistic and morphological differences from other cell death modes, plays a pivotal role in regulating tumorigenesis and offers a new opportunity for modulating anticancer drug resistance. Aberrant epigenetic modifications and posttranslational modifications (PTMs) promote anticancer drug resistance, cancer progression, and metastasis. Accumulating studies indicate that epigenetic modifications can transcriptionally and translationally determine cancer cell vulnerability to ferroptosis and that ferroptosis functions as a driver in nervous system diseases (NSDs), cardiovascular diseases (CVDs), liver diseases, lung diseases, and kidney diseases. In this review, we first summarize the core molecular mechanisms of ferroptosis. Then, the roles of epigenetic processes, including histone PTMs, DNA methylation, and noncoding RNA regulation and PTMs, such as phosphorylation, ubiquitination, SUMOylation, acetylation, methylation, and ADP-ribosylation, are concisely discussed. The roles of epigenetic modifications and PTMs in ferroptosis regulation in the genesis of diseases, including cancers, NSD, CVDs, liver diseases, lung diseases, and kidney diseases, as well as the application of epigenetic and PTM modulators in the therapy of these diseases, are then discussed in detail. Elucidating the mechanisms of ferroptosis regulation mediated by epigenetic modifications and PTMs in cancer and other diseases will facilitate the development of promising combination therapeutic regimens containing epigenetic or PTM-targeting agents and ferroptosis inducers that can be used to overcome chemotherapeutic resistance in cancer and could be used to prevent other diseases. In addition, these mechanisms highlight potential therapeutic approaches to overcome chemoresistance in cancer or halt the genesis of other diseases.

Overcoming cancer chemotherapy resistance by the induction of ferroptosis.

Development of resistance to chemotherapy in cancer continues to be a major challenge in cancer management. Ferroptosis, a unique type of cell death, is mechanistically and morphologically different from other forms of cell death. Ferroptosis plays a pivotal role in inhibiting tumour growth and has presented new opportunities for treatment of chemotherapy-insensitive tumours in recent years. Emerging studies have suggested that ferroptosis can regulate the therapeutic responses of tumours. Accumulating evidence supports ferroptosis as a potential target for chemotherapy resistance. Pharmacological induction of ferroptosis could reverse drug resistance in tumours. In this review article, we first discuss the key principles of chemotherapeutic resistance in cancer. We then provide a brief overview of the core mechanisms of ferroptosis in cancer chemotherapeutic drug resistance. Finally, we summarise the emerging data that supports the fact that chemotherapy resistance in different types of cancers could be subdued by pharmacologically inducing ferroptosis. This review article suggests that pharmacological induction of ferroptosis by bioactive compounds (ferroptosis inducers) could overcome chemotherapeutic drug resistance. This article also highlights some promising therapeutic avenues that could be used to overcome chemotherapeutic drug resistance in cancer.

NMT1 Enhances the Stemness of NSCLC Cells by Activating the PI3K/AKT Pathway.

INTRODUCTION: Abundant studies have disclosed that proteins can function as pivotal tumor promoters or suppressors in cancers' progression. This work was planned to investigate the regulatory function of N-myristoyltransferase-1 (NMT1) on non-small cell lung cancer (NSCLC) and the underlying molecular mechanisms. METHODS: The self-renewal abilities were assessed through a spheroid-formation assay. The tumorigenic abilities were examined through nude mice in vivo assay. The proteins' expression was measured through Western blot. The NMT1 protein expression in tumor tissues was measured through an IHC assay. The cell migration and invasion was confirmed through a transwell assay. The IC50 was verified through a CCK-8 assay. The NMT1 mRNA expression in NSCLC tissues was detected through RT-qPCR. RESULTS: It was demonstrated that NMT1 exhibited higher expression in spheroid cells. Additionally, NMT1 facilitated the stemness in NSCLC. It was also found that NMT1 accelerated NSCLC tumor metastasis and the resistance to cisplatin. Moreover, NMT1 activated the PI3K/AKT pathway to facilitate stemness in NSCLC. NMT1 was also higher in tumor tissues of NSCLC patients and resulted in a poor survival rate. CONCLUSION: NMT1 enhanced the stemness of NSCLC cells by activating the PI3K/AKT pathway. This discovery suggested that NMT1 may be a valid therapeutic biomarker for NSCLC.