Dual role of the integrated stress response in medulloblastoma tumorigenesis

// Sarrabeth Stone 1, 2, 3, * , Yeung Ho 1, 2, 3, * , Xiting Li 1, 2, 3, 4 , Stephanie Jamison 1, 2, 3 , Heather P. Harding 5 , David Ron 5 , Wensheng Lin 1, 2, 3 1 Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States 2 Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States 3 Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States 4 Department of Periodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China 5 Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom * These authors contributed equally to this work Correspondence to: Wensheng Lin, email: linw@umn.edu Keywords: medulloblastoma, integrated stress response, ER stress, GADD34, tumorigenesis Received: May 27, 2016 Accepted: September 01, 2016 Published: September 06, 2016 ABSTRACT In response to endoplasmic reticulum (ER) stress, activation of pancreatic ER kinase (PERK) coordinates an adaptive program known as the integrated stress response (ISR) by phosphorylating translation initiation factor 2α (eIF2α). Phosphorylated eIF2α is quickly dephosphorylated by the protein phosphatase 1 and growth arrest and DNA damage 34 (GADD34) complex. Data indicate that the ISR can either promote or suppress tumor development. Our previous studies showed that the ISR is activated in medulloblastoma in both human patients and animal models, and that the decreased ISR via PERK heterozygous deficiency attenuates medulloblastoma formation in Patched1 heterozygous deficient ( Ptch1 +/−) mice by enhancing apoptosis of pre-malignant granule cell precursors (GCPs) during cell transformation. We showed here that GADD34 heterozygous mutation moderately enhanced the ISR and noticeably increased the incidence of medulloblastoma in adult Ptch1 +/− mice. Surprisingly, GADD34 homozygous mutation strongly enhanced the ISR, but significantly decreased the incidence of medulloblastoma in adult Ptch1 +/− mice. Intriguingly, GADD34 homozygous mutation significantly enhanced pre-malignant GCP apoptosis in cerebellar hyperplastic lesions and reduced the lesion numbers in young Ptch1 +/− mice. Nevertheless, neither GADD34 heterozygous mutation nor GADD34 homozygous mutation had a significant effect on medulloblastoma cells in adult Ptch1 +/− mice. Collectively, these data imply the dual role of the ISR, promoting and inhibiting, in medulloblastoma tumorigenesis by regulating apoptosis of pre-malignant GCPs during the course of malignant transformation.