Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD

Manuela Salerno, Sofia Avnet, Gloria Bonuccelli, Shigekuni Hosogi, Donatella Granchi, Nicola Baldini

Research output: Contribution to journalArticle

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Abstract

Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children and adolescents, with a high rate of relapse that dramatically affects the clinical outcome. Multiagent chemotherapy, in combination with surgery and/or radiation therapy, is the treatment of choice. However, the relapse rate is disappointingly high and identification of new therapeutic tools is urgently needed. Under this respect, the selective block of key features of cancer stem cells (CSC) appears particularly promising. In this study, we isolated rhabdomyosarcoma CSC with stem-like features (high expression of NANOG and OCT3/ 4, self-renewal ability, multipotency). Rhabdomyosarcoma CSC showed higher invasive ability and a reduced cytotoxicity to doxorubicin in comparison to native cells, through a mechanism unrelated to the classical multidrug resistance process. This was dependent on a high level of lysosome acidity mediated by a high expression of vacuolar ATPase (V-ATPase). Since it was not associated with other paediatric cancers, like Ewing's sarcoma and neuroblastoma, V-ATPase higher expression in CSC was rhabdomyosarcoma specific. Inhibition of lysosomal acidification by the V-ATPase inhibitor omeprazole, or by specific siRNA silencing, significantly enhanced doxorubicin cytoxicity. Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 μM, respectively). Based on these observations, we propose lysosome acidity as a valuable target to enhance chemosensitivity of rhabdomyosarcoma CSC, and suggest the use of anti-V-ATPase agents in combination with standard regimens as a promising tool for the eradication of minimal residual disease or the prevention of metastatic disease.

Original languageEnglish
Article numbere110340
JournalPLoS One
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 20 2014

Fingerprint

Embryonal Rhabdomyosarcoma
Neoplastic Stem Cells
Rhabdomyosarcoma
Stem cells
Vacuolar Proton-Translocating ATPases
stem cells
H-transporting ATP synthase
Cells
cell lines
Cell Line
therapeutics
doxorubicin
Omeprazole
relapse
sarcoma
lysosomes
Lysosomes
Acidity
Doxorubicin
acidity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD. / Salerno, Manuela; Avnet, Sofia; Bonuccelli, Gloria; Hosogi, Shigekuni; Granchi, Donatella; Baldini, Nicola.

In: PLoS One, Vol. 9, No. 10, e110340, 20.10.2014.

Research output: Contribution to journalArticle

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