Inhibition of glycolysis enhances the efficacy of immunotherapy via PDK-mediated upregulation of PD-L1.

BACKGROUND: Immunotherapy for gastric cancer remains a challenge due to its limited efficacy. Metabolic reprogramming toward glycolysis has emerged as a promising avenue for enhancing the sensitivity of tumors to immunotherapy. Pyruvate dehydrogenase kinases (PDKs) play pivotal roles in regulating glycolysis. The importance of PDKs in the context of gastric cancer immunotherapy and their potential as therapeutic targets have not been fully explored. METHODS: PDK and PD-L1 expression was analyzed using data from the GSE66229 and The Cancer Genome Atlas (TCGA) cohorts. Additionally, the Immune Checkpoint Blockade Therapy Atlas (ICBatlas) database was utilized to assess PDK expression in an immune checkpoint blockade (ICB) therapy group. Subsequently, the upregulation of PD-L1 and the enhancement of anticancer effects achieved by targeting PDK were validated through in vivo and in vitro assays. The impact of PDK on histone acetylation was investigated using ChIP‒qPCR to detect changes in histone acetylation levels. RESULTS: Our analysis revealed a notable negative correlation between PD-L1 and PDK expression. Downregulation of PDK led to a significant increase in PD-L1 expression. PDK inhibition increased histone acetylation levels by promoting acetyl-CoA generation. The augmentation of acetyl-CoA production and concurrent inhibition of histone deacetylation were found to upregulate PD-L1 expression in gastric cancer cells. Additionally, we observed a significant increase in the anticancer effect of PD-L1 antibodies following treatment with a PDK inhibitor. CONCLUSIONS: Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy.

Revisiting chemoresistance in ovarian cancer: Mechanism, biomarkers, and precision medicine.

Among the gynecological cancers, ovarian cancer is the most lethal. Its therapeutic options include a combination of chemotherapy with platinum-based compounds and cytoreductive surgery. Most ovarian cancer patients exhibit an initial response to platinum-based therapy, however, platinum resistance has led to up to 80% of this responsive cohort becoming refractory. Ovarian cancer recurrence and drug resistance to current chemotherapeutic options is a global challenge. Chemo-resistance is a complex phenomenon that involves multiple genes and signal transduction pathways. Therefore, it is important to elucidate on the underlying molecular mechanisms involved in chemo-resistance. This inform decisions regarding therapeutic management and help in the identification of novel and effective drug targets. Studies have documented the individual biomarkers of platinum-resistance in ovarian cancer that are potential therapeutic targets. This review summarizes the molecular mechanisms of platinum resistance in ovarian cancer, novel drug targets, and clinical outcomes.

Alkaloids Exhibit a Meaningful Function as Anticancer Agents by Restraining Cellular Signaling Pathways.

Alkaloids are nitrogen-containing organic compounds widely found in natural products, which play an essential role in clinical treatment. Cellular signaling pathways in tumors are a series of enzymatic reaction pathways that convert extracellular signals into intracellular signals to produce biological effects. The ordered function of cell signaling pathways is essential for tumor cell proliferation, differentiation, and programmed death. This review describes the antitumor progression mediated by various alkaloids after inhibiting classical signaling pathways; related studies are systematically retrieved and collected through PubMed. We selected the four currently most popular pathways for discussion and introduced the molecular mechanisms mediated by alkaloids in different signaling pathways, including the NF-kB signaling pathway, PI3K/AKT signaling pathway, MAPK signaling pathway, and P53 signaling pathway. The research progress of alkaloids related to tumor signal transduction pathways and the realization of alkaloids as cancer prevention drugs by targeting signal pathways remains.

Endometrial Cancer: Genetic, Metabolic Characteristics, Therapeutic Strategies and Nanomedicine.

BACKGROUND: Endometrial cancer is the fourth most common malignancy in female population worldwide. It was estimated that 65,620 new cases and 12.590 subsequent deaths occurred in 2020 in the United States. Patients with type II and advanced endometrial cancer do not respond well to the current treatments. Therefore, endometrial cancer should be better understood in order to develop more effective treatments. OBJECTIVE: To provide an overview of genetic, metabolic characteristics, therapeutic strategies and current application of nanotechnology surrounding endometrial cancer. METHODS: Relevant articles were retrieved from Pubmed and were systematically reviewed. RESULTS: Hypoxia inducible factor-1 and Von Hippel-Lindau factor participated in oncogenesis and progression of endometrial cancer and Nrf2 was associated with oncogenesis. Various genetic alterations were found in endometrial cancer. Examining the abnormal X chromosome inactivation may help in the diagnosis of endometrial cancer and its precancerous lesions. Some absent tumor suppressor genes, activated oncogenes were revealed by the genetically modified mouse models. Disorders in glucose and lipid metabolism were found in endometrial cancer. Current therapeutic strategies focused on the HIF-1α pathway, the mTOR pathway as well as the immunotherapy. Nanotechnology showed great potential in endometrial cancer's early diagnosis, metastasis determination and treatment. CONCLUSION: Endometrial cancer has been understood in various aspects but the underlying mechanisms still remain relatively unknown, which might be the source of novel diagnostic, prognostic and therapeutic targets. Nanomedicine in endometrial cancer is poorly studied but the current researches showed great results in treating endometrial cancer. It needs further researching.

XIST: A Meaningful Long Noncoding RNA in NSCLC Process.

BACKGROUND: A number of studies have proposed that lncRNA XIST plays a role in the development and chemosensitivity of NSCLC. Besides, XIST may become a potential therapeutic target for NSCLC patients. The aim of this review is to reveal the biological functions and exact mechanisms of XIST in NSCLC. METHODS: In this review, relevant researches involving the relationship between XIST and NSCLC are collected through systematic retrieval of PubMed. RESULTS: XIST is an oncogene in NSCLC and is abnormally upregulated in NSCLC tissues. Considerable evidence has shown that XIST plays a critical role in the proliferation, invasion, migration, apoptosis and chemosensitivity of NSCLC cells. XIST mainly functions as a ceRNA in the NSCLC process, while XIST also functions at transcriptional levels. CONCLUSION: LncRNA XIST has the potential to become a novel biomolecular marker of NSCLC and a therapeutic target for NSCLC.