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

ABSTRACT: 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.

SUBMITTER: Rajendra J

PROVIDER: S-EPMC6021241 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Rajendra Jacinth J Datta Keshava K KK Ud Din Farooqee Sheikh Burhan SB Thorat Rahul R Kumar Kiran K Gardi Nilesh N Kaur Ekjot E Nair Jyothi J Salunkhe Sameer S Patkar Ketaki K Desai Sanket S Goda Jayant Sastri JS Moiyadi Aliasgar A Dutt Amit A Venkatraman Prasanna P Gowda Harsha H Dutt Shilpee S

Oncotarget 20180612 45

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 ...[more]

PMID: 29963228

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Project description:Despite optimal clinical treatment, glioblastoma multiforme (GBM) inevitably recurs. Standard treatment of GBM, exposes patients to radiation which kills tumor cells, but also modulates the molecular fingerprint of any surviving tumor cells and the cross-talk between those cells and the host. Considerable investigation of short-term (hours to days) post-irradiation tumor cell response has been undertaken, yet long-term responses (weeks to months) which are potentially even more informative of recurrence, have been largely overlooked. To better understand the potential of these processes to reshape tumor regrowth, molecular studies in conjunction with in silico modeling were used to examine short- and long-term growth dynamics. Despite survival of 2.55% and 0.009% following 8 or 16Gy, GBM cell populations in vitro showed a robust escape from cellular extinction and a return to pre-irradiated growth rates with no changes in long-term population doublings. In contrast, these same irradiated GBM cell populations injected in vivo elicited tumors which displayed significantly suppressed growth rates compared to their pre-irradiated counterparts. Transcriptome analysis days to weeks after irradiation revealed, 281 differentially expressed genes with a robust increase for cytokines, histones and C-C or C-X-C motif chemokines in irradiated cells. Strikingly, this same inflammatory signature in vivo for IL1A, CXCL1, IL6 and IL8 was increased in xenografts months after irradiation. Computational modeling of tumor cell dynamics indicated a host-mediated negative pressure on the surviving cells was a source of inhibition consistent with the findings resulting in suppressed tumor growth. Thus, tumor cells surviving irradiation may shift the landscape of population doubling through inflammatory mediators interacting with the host in a way that impacts tumor recurrence and affects the efficacy of subsequent therapies. Clues to more effective therapies may lie in the development and use of pre-clinical models of post-treatment response to target the source of inflammatory mediators that significantly alter cellular dynamics and molecular pathways in the early stages of tumor recurrence.

Project description:Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21-/- mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion in vitro, which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes in vivo, significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. SIGNIFICANCE: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.

Dataset Information

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

Publications

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

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