GLP1R boosts survival, migration and invasion of endometrial cancer cells and protects against ferroptotic cell death.

BACKGROUND: Despite the strong evidence concerning carcinogenic roles of glucagon-like peptide 1 receptor (GLP1R), the role of this gene in endometrial cancer (EC) remains elusive. This study investigated the properties of GLP1R on EC in vitro. METHODS: The expression of GLP1R in EC was detected by RT-qPCR, immunohistochemistry, and western blotting. Cell viability, cell cycle, apoptosis, migration, invasion and ferroptosis were assessed through CCK-8, flow cytometry, wound healing, transwell, DCFH-DA and western blotting, respectively. RESULTS: We found that GLP1R was up-regulated in EC than normal specimens. It had the highest expression in AN3CA cells. Cell viability, migration and invasion were significantly reduced, while cell cycle arrest and apoptosis were induced following GLP1R knockdown. The malignant biological behaviours of AN3CA cells were investigated when treated with exendin-4 (GLP1R agonist). Moreover, GLP1R lowered intracellular ROS level and expression of SLC7A11, and FTH1, but mitigated GPX4 expression in AN3CA cells. CONCLUSION: In a word, GLP1R was up-regulated in EC and its up-regulation facilitated the proliferative and metastatic potentials, and protected cells from ferroptosis, thereby accelerating EC progression. These data emphasised the potency of GLP1R as a therapeutic agent against EC.

Endometrial cancer (EC) is the second most common form of gynaecologic malignancy, with over 189,000 new cases and about 45,000 deaths worldwide per annum. The effects of glucagon-like peptide 1 receptor (GLP1R) in cancers such as colon and pancreatic cancers have been uncovered. However, whether GLP1R affects EC progression especially ferroptosis process remains elusive. In this study, up-regulation of GLP1R promotes the proliferative and metastatic potentials of EC cells, and protects EC cells from ferroptosis. The opposite results are observed in GLP1R knocking-down. Our study found that GLP1R may exert an oncogene function in EC cells, which can affect proliferative, migrated as well as invasive capacities of EC cells. Moreover, it protected EC cells from ferroptosis. Thus, our results expanded the understanding of the function of GLP1R protein and offered insights into the targeted treatment strategies against EC.

Identification of glycogen phosphorylase L as a potential target for lung cancer.

Traditional Chinese medicine (TCM) has been widely used for cancer treatment. Identification of anti-cancer targets of TCM is the first and principal step in discovering molecular mechanisms of TCM as well as obtaining novel targets for cancer therapy. In this study, glycogen phosphorylase L (PYGL) was identified as one of the targeted proteins for several TCMs and was upregulated in various cancer types. The expression level of PYGL was positively correlated with the stage of lung cancer and the poor prognosis of patients. Meanwhile, knockdown of PYGL significantly inhibited proliferation and migration in lung cancer cells. In addition, PYGL was associated with spindle, kinetochore, and microtubule, the cellular components that are closely related to mitosis, in lung cancer. Moreover, PYGL was more susceptible to be upregulated by 144 mutated genes. Taken together, PYGL is a potential target for lung cancer treatment and its molecular mechanism probably influences the mitotic function of cells by regulating energy metabolism.

m6A modification: recent advances, anticancer targeted drug discovery and beyond.

Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, and aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches and modern drug discovery platforms have been used in an attempt to develop m6A-targeted drugs. Here, we provide an update of the latest findings on m6A modification and the critical roles of m6A modification in cancer progression, and we summarize rational sources for the discovery of m6A-targeted anticancer agents from traditional medicines and computer-based chemosynthetic compounds. This review highlights the potential agents targeting m6A modification for cancer treatment and proposes the advantage of artificial intelligence (AI) in the discovery of m6A-targeting anticancer drugs. Three stages of m6A-targeting anticancer drug discovery: traditional medicine-based natural products, modern chemical modification or synthesis, and artificial intelligence (AI)-assisted approaches for the future.

Effect Evaluation of Strychnos nux-vomica L. with Integrative Methods for Bortezomib-Induced Peripheral Neuropathy in Multiple Myeloma Patients: A Self-Controlled Clinical Trial.

OBJECTIVE: To explore the clinical effect and adverse reactions of Strychnos nux-vomica in bortezomib-induced peripheral neuropathy (BIPN) of patients with multiple myeloma (MM). METHODS: A total of 19 MM patients with BIPN were enrolled and Nux Vomica Capsule (NVC, 0.4 g, thrice daily) were orally administrated for 30 days. Comparative analysis on parameters between pre- and post-therapy, including peripheral neuropathy (PN) grade, neurotoxicity score, Chinese medicine (CM) syndrome score, total neuropathy score (TNS), coagulation function, and serum nerve growth factor (NGF) levels were conducted. The adverse events were monitored. RESULTS: In BIPN of MM patients who received NVC, PN grade was lowered, neurotoxicity score was obviously decreased (P⩽0.01), and both CM syndrome score and TNS were remarkably decreased (P<0.01). After the therapy, activated partial thromboplastin time was prolonged (P<0.01) and fibrinogen was declined (P<0.05), showing improvement in the hypercoagulable state of patients. No significant difference of NGF recovery degrees was detected between pre- and post-therapy (P>0.05). No evident adverse reactions were observed during the course of treatment. CONCLUSION: Strychnos nux-vomica L. has significantly effect with a good safety in treatment of BIPN in MM patients.

Natural products as potent inhibitors of hypoxia-inducible factor-1α in cancer therapy.

Hypoxia is a prominent feature of tumors. Hypoxia-inducible factor-1α (HIF-1α), a major subunit of HIF-1, is overexpressed in hypoxic tumor tissues and activates the transcription of many oncogenes. Accumulating evidence has demonstrated that HIF-1α promotes tumor angiogenesis, metastasis, metabolism, and immune evasion. Natural products are an important source of antitumor drugs and numerous studies have highlighted the crucial role of these agents in modulating HIF-1α. The present review describes the role of HIF-1α in tumor progression, summarizes natural products used as HIF-1α inhibitors, and discusses the potential of developing natural products as HIF-1α inhibitors for the treatment of cancer.

Gamabufotalin induces a negative feedback loop connecting ATP1A3 expression and the AQP4 pathway to promote temozolomide sensitivity in glioblastoma cells by targeting the amino acid Thr794.

OBJECTIVES: Temozolomide (TMZ) is one of the most commonly used clinical drugs for glioblastoma (GBM) treatment, but its drug sensitivity needs to be improved. Gamabufotalin (CS-6), the primary component of the traditional Chinese medicine "ChanSu," was shown to have strong anti-cancer activity. However, more efforts should be directed towards reducing its toxicity or effective treatment doses. METHODS: Target fishing experiment, Western blotting, PCR, confocal immunofluorescence and molecular cloning techniques were performed to search for possible downstream signalling pathways. In addition, GBM xenografts were used to further determine the potential molecular mechanisms of the synergistic effects of CS-6 and TMZ in vivo. RESULTS: Mechanistic research revealed a negative feedback loop between ATP1A3 and AQP4 through which CS-6 inhibited GBM growth and mediated the synergistic treatment effect of CS-6 and TMZ. In addition, by mutating potential amino acid residues of ATP1A3, which were predicted by modelling and docking to interact with CS-6, we demonstrated that abrogating hydrogen bonding of the amino acid Thr794 interferes with the activation of ATP1A3 by CS-6 and that the Thr794Ala mutation directly affects the synergistic treatment efficacy of CS-6 and TMZ. CONCLUSIONS: As the main potential target of CS-6, ATP1A3 activation critically depends on the hydrogen bonding of Thr794 with CS-6. The combination of CS-6 and TMZ could significantly reduce the therapeutic doses and promote the anti-cancer efficacy of CS-6/TMZ monotherapy.