Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma

Belamy B. Cheung, Owen Tan, Jessica Koach, Bing Liu, Michael S Y Shum, Daniel R. Carter, Selina Sutton, Sela T. Po'uha, Louis Chesler, Michelle Haber, Murray D. Norris, Maria Kavallaris, Tao Liu, Geraldine M. O'Neill, Glenn M. Marshall

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Retinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40-50% of patients treated with 13- cis-retinoic acid (13- cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR + SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13- cis-RA + SAHA. The 4-HPR + SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tβ4) and decreased mRNA expression of retinoic acid receptor α (RARα). Importantly, the up-regulation of Tβ4 and down-regulation of RARα were both necessary for the 4-HPR + SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tβ4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR + SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tβ4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tβ4 is a novel therapeutic target in neuroblastoma, and that 4-HPR + SAHA is a potential therapy for the disease.

LanguageEnglish
Pages1484-1500
Number of pages17
JournalMolecular Oncology
Volume9
Issue number7
DOIs
Publication statusPublished - 1 Aug 2015
Externally publishedYes

Fingerprint

Fenretinide
Thymosin
Neuroblastoma
Retinoids
Pharmaceutical Preparations
Cell Movement
Isotretinoin
Therapeutics
vorinostat
Messenger RNA
Histone Deacetylase Inhibitors
Focal Adhesions
Residual Neoplasm
Cytoplasmic and Nuclear Receptors
Caspases
Cell Adhesion
Caspase 3
Neoplasms
Up-Regulation
Down-Regulation

Keywords

  • 4-HPR
  • Histone deacetylase inhibitors and retinoic acid receptor alpha (RARα)
  • Neuroblastoma
  • SAHA
  • Thymosin-β4 (Tβ4)

Cite this

Cheung, Belamy B. ; Tan, Owen ; Koach, Jessica ; Liu, Bing ; Shum, Michael S Y ; Carter, Daniel R. ; Sutton, Selina ; Po'uha, Sela T. ; Chesler, Louis ; Haber, Michelle ; Norris, Murray D. ; Kavallaris, Maria ; Liu, Tao ; O'Neill, Geraldine M. ; Marshall, Glenn M. / Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma. In: Molecular Oncology. 2015 ; Vol. 9, No. 7. pp. 1484-1500.
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abstract = "Retinoids are an important component of neuroblastoma therapy at the stage of minimal residual disease, yet 40-50{\%} of patients treated with 13- cis-retinoic acid (13- cis-RA) still relapse, indicating the need for more effective retinoid therapy. Vorinostat, or Suberoylanilide hydroxamic acid (SAHA), is a potent inhibitor of histone deacetylase (HDAC) classes I & II and has antitumor activity in vitro and in vivo. Fenretinide (4-HPR) is a synthetic retinoid which acts on cancer cells through both nuclear retinoid receptor and non-receptor mechanisms. In this study, we found that the combination of 4-HPR + SAHA exhibited potent cytotoxic effects on neuroblastoma cells, much more effective than 13- cis-RA + SAHA. The 4-HPR + SAHA combination induced caspase-dependent apoptosis through activation of caspase 3, reduced colony formation and cell migration in vitro, and tumorigenicity in vivo. The 4-HPR and SAHA combination significantly increased mRNA expression of thymosin-beta-4 (Tβ4) and decreased mRNA expression of retinoic acid receptor α (RARα). Importantly, the up-regulation of Tβ4 and down-regulation of RARα were both necessary for the 4-HPR + SAHA cytotoxic effect on neuroblastoma cells. Moreover, Tβ4 knockdown in neuroblastoma cells increased cell migration and blocked the effect of 4-HPR + SAHA on cell migration and focal adhesion formation. In primary human neuroblastoma tumor tissues, low expression of Tβ4 was associated with metastatic disease and predicted poor patient prognosis. Our findings demonstrate that Tβ4 is a novel therapeutic target in neuroblastoma, and that 4-HPR + SAHA is a potential therapy for the disease.",
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Cheung, BB, Tan, O, Koach, J, Liu, B, Shum, MSY, Carter, DR, Sutton, S, Po'uha, ST, Chesler, L, Haber, M, Norris, MD, Kavallaris, M, Liu, T, O'Neill, GM & Marshall, GM 2015, 'Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma', Molecular Oncology, vol. 9, no. 7, pp. 1484-1500. https://doi.org/10.1016/j.molonc.2015.04.005

Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma. / Cheung, Belamy B.; Tan, Owen; Koach, Jessica; Liu, Bing; Shum, Michael S Y; Carter, Daniel R.; Sutton, Selina; Po'uha, Sela T.; Chesler, Louis; Haber, Michelle; Norris, Murray D.; Kavallaris, Maria; Liu, Tao; O'Neill, Geraldine M.; Marshall, Glenn M.

In: Molecular Oncology, Vol. 9, No. 7, 01.08.2015, p. 1484-1500.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Thymosin-β4 is a determinant of drug sensitivity for Fenretinide and Vorinostat combination therapy in neuroblastoma

AU - Cheung, Belamy B.

AU - Tan, Owen

AU - Koach, Jessica

AU - Liu, Bing

AU - Shum, Michael S Y

AU - Carter, Daniel R.

AU - Sutton, Selina

AU - Po'uha, Sela T.

AU - Chesler, Louis

AU - Haber, Michelle

AU - Norris, Murray D.

AU - Kavallaris, Maria

AU - Liu, Tao

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AU - Marshall, Glenn M.

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