Faculty Collaboration Database

The secreted protein acidic and rich in cysteine (SPARC) induces endoplasmic reticulum stress leading to autophagy-mediated apoptosis in neuroblastoma. Int J Oncol 2013 Jan;42(1):188-96

Date

11/06/2012

Pubmed ID

23123816

Pubmed Central ID

PMC3538858

DOI

10.3892/ijo.2012.1678

Scopus ID

2-s2.0-84873658356 (requires institutional sign-in at Scopus site)   31 Citations

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.

Author List

Sailaja GS, Bhoopathi P, Gorantla B, Chetty C, Gogineni VR, Velpula KK, Gondi CS, Rao JS

MESH terms used to index this publication - Major topics in bold

Apoptosis
Autophagy
Blotting, Western
Caspase 3
Combined Modality Therapy
Endoplasmic Reticulum Stress
Flow Cytometry
Humans
Immunoenzyme Techniques
JNK Mitogen-Activated Protein Kinases
Neuroblastoma
Osteonectin
Phosphorylation
RNA, Messenger
Radiation, Ionizing
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Transcription Factor CHOP
Tumor Cells, Cultured
Unfolded Protein Response