title: The secreted protein acidic and rich in cysteine (SPARC) induces endoplasmic             reticulum stress leading to autophagy-mediated apoptosis in neuroblastoma.
abstract: Our previous studies showed that overexpression of secreted protein acidic and rich in cysteine (SPARC) induced autophagy-mediated apoptosis in PNET cells. In the present study, we attempted to elucidate the molecular mechanisms and signaling cascades associated with SPARC overexpression in combination with radiation therapy that eventually leads to autophagy-mediated apoptosis in neuroblastoma. SPARC expression in SK-N-AS and NB-1691 cells demonstrated the activation of caspase 3, cleavage of PARP and induction of apoptosis. The experiments to unravel the mechanisms associated with autophagy-apoptosis illustrated that SPARC overexpression triggered endoplasmic reticulum (ER) stress and thereby unfolded protein response (UPR). This was apparent with the activation of stress receptors, inositol-requiring enzyme (IRE 1α), RNA-dependent protein kinase (PKR)-like ER kinase (PERK) and BiP. This study further demonstrated the induction of transcription factor CHOP as a result of IRE-JNK activation in response to increased SPARC levels. Inhibition of ER stress and JNK activation led to inhibition of autophagy-mediated apoptosis. Further, the apparent expression of ER stress molecules among the orthotopic tumors treated by SPARC overexpression plasmids substantiated our in vitro observations. Taken together, these results illustrate the critical role of ER stress in regulating autophagy-mediated apoptosis in SPARC-overexpressed neuroblastoma cells and radiation treatment.
authors.affiliation: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine, Peoria, IL 61605, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Sailaja
authors.forename: Praveen
authors.initials: P
authors.lastname: Bhoopathi
authors.forename: Bharathi
authors.initials: B
authors.lastname: Gorantla
authors.forename: Chandramu
authors.initials: C
authors.lastname: Chetty
authors.forename: Venkateswara Rao
authors.initials: VR
authors.lastname: Gogineni
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Velpula
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Gondi
authors.forename: Jasti S
authors.initials: JS
authors.lastname: Rao
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy; D059865:Endoplasmic Reticulum Stress; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: D015676:Osteonectin; D012333:RNA, Messenger; C577241:SPARC protein, human; D051742:Transcription Factor CHOP; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3