Hsp90 regulates the tumorigenic function of tyrosine protein kinase in osteosarcoma

© 2021 John Wiley & Sons Australia, Ltd..

Despite recent advances in diagnosis and treatment, osteosarcoma remains as the most common bone cancer in children and is associated with poor prognosis. Growing evidence has supported dysregulation of threonine and tyrosine protein kinase (TTK) expression as a hallmark of multiple cancers, however, its function in osteosarcoma remains to be elucidated. In the present study, we found that TTK was frequently overexpressed in osteosarcoma and associated with increased tumour growth and progression. Moreover, using both in vitro and in vivo assays, we provided evidence that TTK level was regulated by a molecular chaperone, heat shock protein 90 (Hsp90). Hsp90 directly interacted with TTK and prevents proteasome-dependent TTK degradation, leading to the accumulation of TTK in osteosarcoma cells. Elevated TTK promoted cancer cell proliferation and survival by activating cell-cycle progression and inhibiting apoptosis. Consistently, depletion of TTK by Hsp90 inhibition induced cell-cycle arrest, generated aneuploidy and eventually resulted in apoptotic cancer cell death. Together, our study revealed an important Hsp90-TTK regulatory axis in osteosarcoma cells to promote cancer cell growth and survival. These findings expand our knowledge on osteosarcoma pathogenesis and offer novel therapeutic options for clinical practice.

Medienart:

E-Artikel

Erscheinungsjahr:

2022

Erschienen:

2022

Enthalten in:

Zur Gesamtaufnahme - volume:49

Enthalten in:

Clinical and experimental pharmacology & physiology - 49(2022), 3 vom: 10. März, Seite 380-390

Sprache:

Englisch

Beteiligte Personen:

Yao, Zhao-Peng [VerfasserIn]
Zhu, Hui [VerfasserIn]
Shen, Feng [VerfasserIn]
Gong, Dan [VerfasserIn]

Links:

Volltext

Themen:

Aneuploidy
Apoptosis
Cell cycle
EC 2.7.10.1
HSP90 Heat-Shock Proteins
Heat shock protein 90 (Hsp90)
Journal Article
Osteosarcoma
Protein-Tyrosine Kinases
Threonine and tyrosine protein kinase (TTK)

Anmerkungen:

Date Completed 25.03.2022

Date Revised 25.03.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1111/1440-1681.13613

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM333054938