Abstract Lung cancer is the leading cause of cancer death worldwide, of which lung adenocarcinoma (LUAD) is the most common subtype. Metastasis is the major cause of poor prognosis and mortality for lung cancer patients, which urgently needs great efforts to be further explored. Herein, glutathione peroxidase 8 (GPX8) was identified as a novel potential pro‐metastatic gene in LUAD metastatic mice models from GEO database. GPX8 was highly expressed in tumor tissues, predicting poor prognosis in LUAD patients. Knockdown of GPX8 inhibited LUAD metastasis in vitro and in vivo, while it did not obviously affect tumor growth. Knockdown of GPX8 decreased the levels of p‐FAK and p‐Paxillin and disturbed the distribution of focal adhesion. Furthermore, GPX8 was overexpressed in cancer‐associated fibroblast (CAF) and associated with CAF infiltration in tumor microenvironment of lung cancer. GPX8 silence on fibroblasts suppressed lung cancer cell migration in the coculture system. BRD2 and RRD4 were the potential transcriptionally regulators for GPX8. Bromodomain extra‐terminal inhibitor JQ1 downregulated GPX8 expression and suppressed lung cancer cell migration. Our findings indicate that highly expressed GPX8 in lung cancer cells and fibroblasts functions as a pro‐metastatic factor in lung cancer. JQ1 is identified as a potential inhibitor against GPX8‐mediated lung cancer metastasis.
The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.
The anti-phagocytosis signal, CD47, prevents phagocytosis when it interacts with signal-regulatory protein alpha (SIRPα) on macrophages. Given the vital role of CD47 in immune response, further investigation on the regulation of CD47 in tumor microenvironment is needed. Herein, we identified that interferon-gamma (IFN-γ), one of the most important cytokines in the immune and inflammatory response, up-regulated CD47 expression in cancer cells and this effect could be inhibited by the JAK1/2 inhibitor ruxolitinib, as well as siRNA-mediated silencing of JAK1, STAT1, and IRF1. The IFN-γ-induced surface expression of CD47 contributed to a stronger binding affinity to SIRPα and a decrease in phagocytosis of cancer cells by macrophages. Knockdown of JAK1, STAT1, or IRF1 by siRNA reversed the decreased phagocytosis caused by IFN-γ. Besides, analysis from TCGA revealed that IFNG had a positive correlation with CD47 in various types of cancer, which was supported by the increased surface CD47 expression after IFN-γ treatment in different types of cancer cells. The discovery of IFN-γ-induced up-regulation of CD47 in cancer cells unveils another feedback inhibitory mechanism of IFN-γ, thus providing insights into cancer immunotherapy targeting CD47.
Multiple myeloma (MM) is a hematological malignancy characterized by uncontrolled proliferation of plasma cells and is currently incurable. Despite advancements in therapeutic strategies, resistance to proteasome inhibitors, particularly bortezomib (BTZ), poses a substantial challenge to disease management. This study aimed to explore the efficacy of boanmycin, a novel antitumor antibiotic, in overcoming resistance to BTZ in MM. BTZ-resistant cells were generated over a period of at least 6 months by gradually increasing the concentration of BTZ. The viability of MM cell lines and patient bone marrow mononuclear cells (BMMCs) was measured via the CCK8 reagent. The protein levels of cleaved caspase 3, cleaved caspase 7, cleaved PARP, PARP, p-JNK, JNK, and γ-H2AX were analyzed through Western blot. Cellular morphology was observed via transmission electron microscopy. Colony formation ability was evaluated, and cell apoptosis and the cell cycle were detected through flow cytometry. Xenograft experiments were conducted to evaluate the growth of MM cells in vivo. Our results demonstrated that boanmycin effectively inhibited cell proliferation and colony formation, and triggered apoptosis in both BTZ-sensitive and BTZ-resistant MM cells. The combination of boanmycin with BTZ had greater inhibitory effects than either drug alone. Furthermore, boanmycin significantly suppressed MM cell growth in immunodeficient mouse xenograft models without inducing distinct toxic side effects. Notably, boanmycin markedly killed patient-derived MM cells ex vivo. Mechanistically, boanmycin not only disrupts the cell cycle and causes DNA damage but also exerts its antitumor effects by inducing endoplasmic reticulum (ER) functional impairment. Our findings highlight the potential of boanmycin as a promising novel therapeutic option for treating MM, particularly in patients with BTZ resistance.
One new flavanonol 4 H-1-benzopyran-4-one,2-(4-hydroxyphenyl)-3,7-dihydroxy-5-methoxy-8-[5-methyl-2-(1-methylethenyl)-4-hexenyl](21), and twenty-six known compounds 1-20, 22-27 were isolated from the dried root of Sophora flavescens (S. flavescens) in this chemical study. Their structures were elucidated according to the spectroscopic and spectrometric methods. All the isolated compounds were evaluated for their cytotoxicity against lung cancer A549 cells and colon cancer HCT116 cells. Among them, compound 21 showed relatively predominant cell proliferation inhibition effect on the two tumor cell lines. Moreover, it induced cells apoptosis as evidenced by the Annexin V/PI double staining assay as well as the increased cleaved-PARP expression. The aforementioned data indicated that the flavonoids of S. flavescens have potential anti-cancer effect.
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