D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis

Shuxi Qiao, Christopher M. Cabello, Sarah D. Lamore, Jessica L. Lesson, Georg T Wondrak

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

D-Penicillamine (3,3-dimethyl-D-cysteine; DP) is an FDA-approved redox-active D-cysteine-derivative with antioxidant, disulfide-reducing, and metal chelating properties used therapeutically for the control of copper-related pathology in Wilson's disease and reductive cystine- solubilization in cystinuria. Based on the established sensitivity of metastatic melanoma cells to pharmacological modulation of cellular oxidative stress, we tested feasibility of using DP for chemotherapeutic intervention targeting human A375 melanoma cells in vitro and in vivo. DP treatment induced caspase-dependent cell death in cultured human metastatic melanoma cells (A375, G361) without compromising viability of primary epidermal melanocytes, an effect not observed with the thiol-antioxidants N-acetyl-L-cysteine (NAC) and dithiothreitol. Focused gene expression array analysis followed by immunoblot detection revealed that DP rapidly activates the cytotoxic unfolded protein response (UPR; involving phospho-PERK, phospho-eIF2a, Grp78, CHOP, and Hsp70) and the mitochondrial pathway of apoptosis with p53 upregulation and modulation of Bcl-2 family members (involving Noxa, Mcl-1, and Bcl-2). DP (but not NAC) induced oxidative stress with early impairment of glutathione homeostasis and mitochondrial transmembrane potential. SiRNA-based antagonism of PMAIP1 expression blocked DP-induced upregulation of the proapoptotic BH3-only effector Noxa and prevented down-regulation of the Noxa-antagonist Mcl-1, rescuing melanoma cells from DP-induced apoptosis. Intraperitoneal administration of DP displayed significant antimelanoma activity in a murine A375 xenograft model. It remains to be seen if melanoma cell-directed induction ofUPR and apoptosis using DPor improved DP-derivatives can be harnessed for future chemotherapeutic intervention.

Original languageEnglish (US)
Pages (from-to)1079-1094
Number of pages16
JournalApoptosis
Volume17
Issue number10
DOIs
StatePublished - Oct 2012

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Noxae
Unfolded Protein Response
Penicillamine
Melanoma
Oxidative stress
Acetylcysteine
Apoptosis
Cysteine
Antioxidants
Modulation
Derivatives
Proteins
Cystine
Dithiothreitol
Pathology
Cell death
Caspases
Chelation
Sulfhydryl Compounds
Heterografts

Keywords

  • Apoptosis
  • D-Penicillamine
  • Mcl-1
  • Metastatic melanoma
  • Noxa (PMAIP1)
  • Unfolded protein response (UPR)

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry
  • Biochemistry, medical
  • Cancer Research
  • Pharmaceutical Science
  • Pharmacology

Cite this

D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. / Qiao, Shuxi; Cabello, Christopher M.; Lamore, Sarah D.; Lesson, Jessica L.; Wondrak, Georg T.

In: Apoptosis, Vol. 17, No. 10, 10.2012, p. 1079-1094.

Research output: Contribution to journalArticle

Qiao, Shuxi ; Cabello, Christopher M. ; Lamore, Sarah D. ; Lesson, Jessica L. ; Wondrak, Georg T. / D-Penicillamine targets metastatic melanoma cells with induction of the unfolded protein response (UPR) and Noxa (PMAIP1)-dependent mitochondrial apoptosis. In: Apoptosis. 2012 ; Vol. 17, No. 10. pp. 1079-1094.
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