title: Down-modulation of SEL1L, an unfolded protein response and endoplasmic reticulum-associated degradation protein, sensitizes glioma stem cells to the cytotoxic effect of valproic acid.
abstract: Valproic acid (VPA), an histone deacetylase inhibitor, is emerging as a promising therapeutic agent for the treatments of gliomas by virtue of its ability to reactivate the expression of epigenetically silenced genes. VPA induces the unfolded protein response (UPR), an adaptive pathway displaying a dichotomic yin yang characteristic; it initially contributes in safeguarding the malignant cell survival, whereas long-lasting activation favors a proapoptotic response. By triggering UPR, VPA might tip the balance between cellular adaptation and programmed cell death via the deregulation of protein homeostasis and induction of proteotoxicity. Here we aimed to investigate the impact of proteostasis on glioma stem cells (GSC) using VPA treatment combined with subversion of SEL1L, a crucial protein involved in homeostatic pathways, cancer aggressiveness, and stem cell state maintenance. We investigated the global expression of GSC lines untreated and treated with VPA, SEL1L interference, and GSC line response to VPA treatment by analyzing cell viability via MTT assay, neurosphere formation, and endoplasmic reticulum stress/UPR-responsive proteins. Moreover, SEL1L immunohistochemistry was performed on primary glial tumors. The results show that (i) VPA affects GSC lines viability and anchorage-dependent growth by inducing differentiative programs and cell cycle progression, (ii) SEL1L down-modulation synergy enhances VPA cytotoxic effects by influencing GSCs proliferation and self-renewal properties, and (iii) SEL1L expression is indicative of glioma proliferation rate, malignancy, and endoplasmic reticulum stress statuses. Targeting the proteostasis network in association to VPA treatment may provide an alternative approach to deplete GSC and improve glioma treatments.
authors: From the Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, 20138 Milan, Italy.
authors: Monica
authors: M
authors: Cattaneo
authors: Simona
authors: S
authors: Baronchelli
authors: Davide
authors: D
authors: Schiffer
authors: Marta
authors: M
authors: Mellai
authors: Valentina
authors: V
authors: Caldera
authors: Gloria Jotti
authors: GJ
authors: Saccani
authors: Leda
authors: L
authors: Dalpra
authors: Antonio
authors: A
authors: Daga
authors: Rosaria
authors: R
authors: Orlandi
authors: Pasquale
authors: P
authors: DeBlasio
authors: Ida
authors: I
authors: Biunno
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000502:physiology; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D004791:Enzyme Inhibitors; D011506:Proteins; C117384:SEL1L protein, human; D014635:Valproic Acid
keywords: Brain Tumors; Cancer Stem Cells; Cell Proliferation; Drug Resistance; Histone Deacetylase