2. Academic Validation
  3. The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells

The IRE1 and PERK arms of the unfolded protein response promote survival of rhabdomyosarcoma cells

  • Cancer Lett. 2020 Oct 10;490:76-88. doi: 10.1016/j.canlet.2020.07.009.
Nicole McCarthy 1,  Nadezda Dolgikh 1,  Susan Logue 2,  John B Patterson 3,  Qinping Zeng 4,  Adrienne M Gorman 5,  Afshin Samali 5,  Simone Fulda 6
Affiliations

Affiliations

  • 1 Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528, Frankfurt, Germany.
  • 2 Rady Faculty of Health Sciences, University of Manitoba, Canada.
  • 3 Orinove Inc., Newbury Park, CA, USA.
  • 4 Fosun Orinove PharmaTech Inc., Suzhou, Jiangsu, China.
  • 5 Apoptosis Research Centre, National University of Ireland Galway, Galway, Ireland; School of Natural Sciences, National University of Ireland Galway, Galway, Ireland.
  • 6 Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528, Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: simone.fulda@kgu.de.
PMID: 32679165 DOI: 10.1016/j.canlet.2020.07.009
Abstract

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma, is associated with a low 5-year survival and harsh treatment side effects, underscoring an urgent need for therapy. The unfolded protein response (UPR) is activated in response to endoplasmic reticulum (ER) stress, where three ER stress receptors, IRE1, PERK and ATF6, aim to restore cellular homeostasis. The UPR is pro-tumourigenic in many cancers. In this study, we investigate basal UPR activity in RMS. Basal activation of IRE1 and PERK was observed in RMS cell lines, which was diminished upon addition of the IRE1 RNase Inhibitor, MKC8866, or PERK Inhibitor, AMGEN44. UPR inhibition caused a reduction in cell viability, cell proliferation and inhibition of long-term colony formation in both subtypes of RMS. Alveolar RMS (ARMS) subtype was highly sensitive to IRE1 inhibition, whereas embryonal RMS (ERMS) subtypes responded more markedly to PERK inhibition. Further investigation revealed a robust activation of senescence upon UPR inhibition. For the first time, the UPR is implicated in RMS biology and phenotype, and inhibition of UPR signalling reduces cell growth, suggesting that the UPR may be a promising target in RMS.

Keywords

Cancer; IRE1; PERK; Rhabdomyosarcoma; Unfolded protein response.

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  • HY-104040
    99.84%, IRE1 RNase抑制剂
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