ABSTRACT
Improving the chemotherapy resistance of temozolomide (TMZ) is of great significance in the treatment of glioblastoma multiforme (GBM). Long non-coding RNA just proximal to the X-inactive specific transcript (JPX) has been proven to be involved in cancer progression. However, the intrinsic significance and molecular mechanism by which JPX orchestrates GBM progression and TMZ chemotherapy resistance remain poorly understood. Here, JPX was found to be significantly elevated in GBM tissues and cell lines, and patients with high expressions of JPX showed significantly worse prognoses. Functional experiments revealed its carcinogenic roles in GBM cell proliferation, TMZ chemoresistance, anti-apoptosis, DNA damage repair, and aerobic glycolysis. Mechanistically, JPX formed a complex with phosphoinositide dependent kinase-1 (PDK1) messenger RNA (mRNA) and promoted its stability and expression. Furthermore, an RNA immunoprecipitation (RIP) experiment showed that JPX interacted with N6-methyladenosine (m6A) demethylase FTO alpha-ketoglutarate dependent dioxygenase (FTO) and enhanced FTO-mediated PDK1 mRNA demethylation. JPX exerted its GBM-promotion effects through the FTO/PDK1 axis. Taken together, these findings reveal the key role of JPX in promoting GBM aerobic glycolysis and TMZ chemoresistance in an m6A-dependent manner. Thus, it comprises a promising novel therapeutic target for GBM chemotherapy.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , RNA, Long Noncoding/metabolism , Temozolomide/pharmacology , Adenosine/analogs & derivatives , Adenosine/metabolism , Aerobiosis , Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Cell Line, Tumor , Demethylation , Disease Progression , Drug Resistance, Neoplasm , Glioblastoma/drug therapy , Glioblastoma/mortality , Glioblastoma/pathology , Glycolysis , Humans , Neoplasm Proteins/metabolism , Prognosis , RNA, Messenger/metabolismABSTRACT
Six new bisabolane-type phenolic sesquiterpenoids, including plakordiols A-D (1-4), (7R, 10R)-hydroxycurcudiol (5) and (7R, 10S)-hydroxycurcudiol (6) were isolated from the marine sponge Plakortis simplex collected from the South China Sea. Their structures were determined based on extensive analysis of spectroscopic data. Their configurations were assigned by coupling constant analysis, NOESY correlations, and the modified Mosher's method. Furthermore, their cytotoxic and antibacterial activities were evaluated.
