Please use this identifier to cite or link to this item: https://doi.org/10.18632/oncotarget.793
Title: Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition
Authors: Mohan, P
Castellsague, J
Jiang, J
Allen, K
Chen, H 
Nemirovsky, O
Spyra, M
Hu, K
Kluwe, L
Pujana, M.A
Villanueva, A
Mautner, V.F
Keats, J.J
Dunn, S.E
Lazaro, C
Maxwell, C.A
Keywords: alisertib
aurora A kinase
hyaluronan mediated motility receptor protein
targeting protein for XKLP2
tumor protein
unclassified drug
animal cell
animal experiment
animal model
apoptosis
article
cancer cell culture
cancer inhibition
cancer stem cell
cell cycle regulation
cell differentiation
cell renewal
controlled study
drug sensitization
endoreduplication
enzyme activity
enzyme inhibition
gene
gene dosage
gene expression regulation
gene mutation
gene product
gene silencing
genetic disequilibrium
hyaluronan mediated motility receptor gene
in vivo study
male
malignant peripheral nerve sheath tumor
mouse
nonhuman
Issue Date: 2013
Publisher: Impact Journals LLC
Citation: Mohan, P, Castellsague, J, Jiang, J, Allen, K, Chen, H, Nemirovsky, O, Spyra, M, Hu, K, Kluwe, L, Pujana, M.A, Villanueva, A, Mautner, V.F, Keats, J.J, Dunn, S.E, Lazaro, C, Maxwell, C.A (2013). Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition. Oncotarget 4 (1) : 80-93. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.793
Rights: Attribution 4.0 International
Abstract: Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and selfrenewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM. © Mohan et al.
Source Title: Oncotarget
URI: https://scholarbank.nus.edu.sg/handle/10635/177785
ISSN: 19492553
DOI: 10.18632/oncotarget.793
Rights: Attribution 4.0 International
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