title: Progranulin promotes Temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness.
abstract: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples. PGRN overexpression conferred GBM cells with tumorigenic properties and TMZ resistance by upregulating DNA repair (PARP, ATM, BRCA1, Rad51, XRCC1 and so on) and cancer stemness (CD133, CD44, ABCG2) genes, in part via an AP-1 transcription factor, specifically cFos/JunB. Curcumin, an AP-1 inhibitor, was also found to regulate PGRN promoter activity and expression including its downstream effectors aforementioned. These data suggested a feedforward loop between PGRN signaling and AP-1. PGRN depletion significantly decreased unlimited self-renewal and multilineage differentiation and the malignant properties of GBMs cells S1R1, and enhanced their vulnerability to TMZ. In addition, S1R1 depleted of PGRN also lost the ability to form tumor in an orthotopic xenograft mouse model. In conclusion, PGRN had a critical role in the pathogenesis and chemoresistance of GBM and functioned at the top of the hierarchy of cellular machinery that modulates both DNA repair pathways and cancer stemness. Our data suggest that a new strategy combining current regimens with compounds targeting PGRN/AP-1 loop like curcumin may significantly improve the therapeutic outcome of GBM.
authors.affiliation: 1] Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan [2] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: I
authors.initials: I
authors.lastname: Bandey
authors.affiliation: Department of Ophthalmology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan.
authors.forename: S-H
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Section of Neurosurgery, Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: A-P
authors.initials: AP
authors.lastname: Huang
authors.affiliation: 1] Section of Neurosurgery, Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan [2] Center for Optoelectronic Medicine, National Taiwan University College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: J-C
authors.initials: JC
authors.lastname: Tsai
authors.affiliation: 1] Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan [2] Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: P-h
authors.initials: PH
authors.lastname: Tu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D003474:Curcumin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000166:cytology*; D000077153:Progranulins; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D000077204:Temozolomide; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; C064269:FOSB protein, human; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; C581727:JunB protein, human; D000077153:Progranulins; D016760:Proto-Oncogene Proteins c-fos; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D003606:Dacarbazine; D003474:Curcumin; D000077204:Temozolomide