The polymerase 1 and transcript release factor (PTRF)-cytoplasmic phospholipase A2 (cPLA2) phospholipid remodeling pathway facilitates tumor proliferation in glioma. Nevertheless, blockade of this pathway leads to the excessive activation of oncogenic receptors on the plasma membrane and subsequent drug resistance. Here, CD26/dipeptidyl peptidase 4 (DPP4) was identified through screening of CRISPR/Cas9 libraries. Suppressing PTRF-cPLA2 signaling resulted in the activation of the epidermal growth factor receptor (EGFR) pathway through phosphatidylcholine and lysophosphatidylcholine remodeling, which ultimately increased DPP4 transcription. In turn, DPP4 interacted with EGFR and prevented its ubiquitination. Linagliptin, a DPP4 inhibitor, facilitated the degradation of EGFR by blocking its interaction with DPP4. When combined with the cPLA2 inhibitor AACOCF3, it exhibited synergistic effects and led to a decrease in energy metabolism in glioblastoma cells. Subsequent in vivo investigations provided further evidence of a synergistic impact of linagliptin by augmenting the sensitivity of AACOCF3 and strengthening the efficacy of temozolomide. DPP4 serves as a novel target and establishes a constructive feedback loop with EGFR. Linagliptin is a potent inhibitor that promotes EGFR degradation by blocking the DPP4-EGFR interaction. This study presents innovative approaches for treating glioma by combining linagliptin with AACOCF3 and temozolomide.

Heat shock protein A9 (HSPA9), a member of the heat shock protein family, is a putative receptor for Tembusu virus (TMUV). By using Western blot and co-immunoprecipitation assays, E protein domains I and II were identified as the functional domains that facilitate HSPA9 binding. Twenty-five overlapping peptides covering domain I and domain II sequences were synthesized and analyzed by using an HSPA9 binding assay. Two peptides showed the capability of binding to HSPA9. Dot blot assay of truncated peptides indicated that amino acid residues 19 to 22 and 245 to 252 of E protein constitute the minimal motifs required for TMUV binding to HSPA9. Importantly, peptides harboring those two minimal motifs could effectively inhibit TMUV infection. Our results provide insight into TMUV-receptor interaction, thereby creating opportunities for elucidating the mechanism of TMUV entry.
Blotting, Western ; Heat-Shock Proteins ; Hot Temperature ; Humans ; Immunoprecipitation ; Peptides ; Protein Structure, Tertiary

Objective To investigate the effect of histone deacetylase inhibitor LBH589 on proliferation,apoptosis and drug resistance of chemoresistant acute myeloid leukemia cells HL60/ADM.Methods HL60/ADM cells were treated with LBH589.Proliferation,apoptosis and adriamycin IC50 were evaluated by MTT assay and AnnexinV-FITC/PI stain.The change in MRP1 expression and intercellular adriamycin accumulatiom were analyzed by flow cytometry.Results Effective proliferative inhibition and apoptotic induction in HL60/ADM cells were observed after treatment with 10-80 nmol/L LBH589 with maximal effect detected after treatment with 70 nmol/L LBH589 for 60 hours.However,inhibition ratio remain unchanged with the further increase of drug dose and incubation time (P ＞ 0.05).Downregulation of MRP1 [(93.90±4.20) ％ vs (76.19±6.53) ％],upregulation of adriamycin accumulation [(8.53±0.68) ％ vs (25.67±1.34) ％] and decrease in adriamycin IC50 [(6.833±0.319) μg/ml vs (1.382±0.104) μg/ml] were induced by the treatment with 20 nmol/L LBH589 (P ＜ 0.01),whose reversal fold was 4.9.The expression of acetylated histone 3 after treatment with LBH589 was higher than that before treatment (P ＜ 0.01).However,relative p-Akt levels after treatment for 24 h and 48 h were 1.07±0.09 and 0.59±0.01,respectively,which were lower than that before treatment (2.03±0.12) (P ＜ 0.01).Meanwhile,expression levels of p53 were 0.57±0.04 and 1.31±0.09,respectively,which were higher than that before treatment (0.21 ±0.02) (P ＜ 0.01).Conclusion Treatment with LBH589 has the capability of inhibiting proliferation and inducing apoptosis,as well as increasing intercellular adriamycin accumulation and sensitivity through downregulation of MRP1 expression and inhibition of PI3K-Akt signaling pathway in HL60/ADM cells.