Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition

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 -