Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition
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Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition. / Mohan, Pooja; Castellsague, Joan; Jiang, Jihong; Allen, Kristi; Chen, Helen; Nemirovsky, Oksana; Spyra, Melanie; Hu, Kaiji; Kluwe, Lan; Pujana, Miguel Angel; Villanueva, Alberto; Mautner, Victor-Felix; Keats, Jonathan J; Dunn, Sandra E; Lazaro, Conxi; Maxwell, Christopher A.
In: ONCOTARGET, Vol. 4, No. 1, 01.01.2013, p. 80-93.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition
AU - Mohan, Pooja
AU - Castellsague, Joan
AU - Jiang, Jihong
AU - Allen, Kristi
AU - Chen, Helen
AU - Nemirovsky, Oksana
AU - Spyra, Melanie
AU - Hu, Kaiji
AU - Kluwe, Lan
AU - Pujana, Miguel Angel
AU - Villanueva, Alberto
AU - Mautner, Victor-Felix
AU - Keats, Jonathan J
AU - Dunn, Sandra E
AU - Lazaro, Conxi
AU - Maxwell, Christopher A
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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 self-renewal 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.
AB - 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 self-renewal 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.
KW - Animals
KW - Antigens, CD44
KW - Aurora Kinase A
KW - Aurora Kinases
KW - Azepines
KW - Cell Cycle Proteins
KW - Cell Differentiation
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Dose-Response Relationship, Drug
KW - Extracellular Matrix Proteins
KW - Gene Expression Regulation, Neoplastic
KW - Humans
KW - Immunoblotting
KW - Male
KW - Mice
KW - Mice, Inbred NOD
KW - Mice, SCID
KW - Microscopy, Confocal
KW - Microtubule-Associated Proteins
KW - Nerve Sheath Neoplasms
KW - Nuclear Proteins
KW - Piperazines
KW - Protein-Serine-Threonine Kinases
KW - Pyrimidines
KW - RNA Interference
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Tumor Burden
KW - Xenograft Model Antitumor Assays
M3 - SCORING: Journal article
C2 - 23328114
VL - 4
SP - 80
EP - 93
JO - ONCOTARGET
JF - ONCOTARGET
SN - 1949-2553
IS - 1
ER -