Enhanced proteasomal activity is essential for long term survival and recurrence of innately radiation resistant residual glioblastoma cells.

Autor:	Rajendra J; Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Datta KK; Institute of Bioinformatics, International Technology Park, Bangalore, India., Ud Din Farooqee SB; Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Thorat R; Laboratory Animal Facility, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India., Kumar K; Institute of Bioinformatics, International Technology Park, Bangalore, India., Gardi N; Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India., Kaur E; Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Nair J; Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Salunkhe S; Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Patkar K; Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India., Desai S; Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Goda JS; Department of Radiation Oncology, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India., Moiyadi A; Department of neurosurgery Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India., Dutt A; Integrated Genomics Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Venkatraman P; Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India., Gowda H; Institute of Bioinformatics, International Technology Park, Bangalore, India., Dutt S; Shilpee Dutt Laboratory, Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India.; Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, India.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2018 Jun 12; Vol. 9 (45), pp. 27667-27681. Date of Electronic Publication: 2018 Jun 12 (Print Publication: 2018).
DOI:	10.18632/oncotarget.25351
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST Authors declare no conflicts of interest.
Databáze:	MEDLINE
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