Progranulin promotes Temozolomide resistance of glioblastoma by orchestrating DNA repair and tumor stemness
Journal
Oncogene
Journal Volume
34
Journal Issue
14
Pages
1853-1864
Date Issued
2014
Author(s)
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. ? 2015 Macmillan Publishers Limited.
SDGs
Other Subjects
alkylating agent; antineoplastic agent; curcumin; dacarbazine; FOSB protein, human; GRN protein, human; JunB protein, human; protein c fos; signal peptide; small interfering RNA; temozolomide; transcription factor; transcription factor AP 1; adult; aged; analogs and derivatives; animal; antagonists and inhibitors; biosynthesis; cancer stem cell; cell motion; cell proliferation; cytology; DNA damage; DNA repair; drug effects; drug resistance; female; genetics; glioblastoma; human; male; metabolism; middle aged; mouse; nonobese diabetic mouse; pathology; promoter region; RNA interference; SCID mouse; tumor cell culture; Adult; Aged; Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Cell Movement; Cell Proliferation; Curcumin; Dacarbazine; DNA Damage; DNA Repair; Drug Resistance, Neoplasm; Female; Glioblastoma; Humans; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Neoplastic Stem Cells; Promoter Regions, Genetic; Proto-Oncogene Proteins c-fos; RNA Interference; RNA, Small Interfering; Transcription Factor AP-1; Transcription Factors; Tumor Cells, Cultured
Publisher
Nature Publishing Group
Type
journal article