Enhanced proteasomal activity is essential for long term survival and recurrence of innately radiation resistant residual glioblastoma cells
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Jacinth Rajendra1,7, Keshava K. Datta2, Sheikh Burhan Ud Din Farooqee3,7, Rahul Thorat5, Kiran Kumar2, Nilesh Gardi4, Ekjot Kaur1,7, Jyothi Nair1,7, Sameer Salunkhe1,7, Ketaki Patkar1, Sanket Desai4,7, Jayant Sastri Goda8, Aliasgar Moiyadi6, Amit Dutt4,7, Prasanna Venkatraman3,7, Harsha Gowda2 and Shilpee Dutt1,7
1Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India
2Institute of Bioinformatics, International Technology Park, Bangalore, India
3Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India
4Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India
5Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India
6Department of neurosurgery Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
7Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India
8Department of Radiation Oncology, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
Shilpee Dutt, email: [email protected]
Keywords: glioblastoma; radio-resistant cells; recurrence; proteomic analysis; proteasomes
Received: August 28, 2017 Accepted: April 25, 2018 Published: June 12, 2018
Therapy resistance and recurrence in Glioblastoma is due to the presence of residual radiation resistant cells. However, because of their inaccessibility from patient biopsies, the molecular mechanisms driving their survival remain unexplored. Residual Radiation Resistant (RR) and Relapse (R) cells were captured using cellular radiation resistant model generated from patient derived primary cultures and cell lines. iTRAQ based quantitative proteomics was performed to identify pathways unique to RR cells followed by in vitro and in vivo experiments showing their role in radio-resistance. 2720 proteins were identified across Parent (P), RR and R population with 824 and 874 differential proteins in RR and R cells. Unsupervised clustering showed proteasome pathway as the most significantly deregulated pathway in RR cells. Concordantly, the RR cells displayed enhanced expression and activity of proteasome subunits, which triggered NFkB signalling. Pharmacological inhibition of proteasome activity led to impeded NFkB transcriptional activity, radio-sensitization of RR cells in vitro, and significantly reduced capacity to form orthotopic tumours in vivo. We demonstrate that combination of proteasome inhibitor with radio-therapy abolish the inaccessible residual resistant cells thereby preventing GBM recurrence. Furthermore, we identified first proteomic signature of RR cells that can be exploited for GBM therapeutics.
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