Chloroquine promotes apoptosis in melanoma cells by inhibiting BH3 domain-mediated PUMA degradation

Alexander J. Lakhter, Ravi P. Sahu, Yang Sun, William K. Kaufmann, Elliot J. Androphy, Jeffrey B. Travers, Samisubbu R. Naidu

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The Bcl homology-3 (BH3)-only protein p53 upregulated modulator of apoptosis (PUMA) counters Bcl-2 family anti-apoptotic proteins and promotes apoptosis. Although PUMA is a key regulator of apoptosis, the post-transcriptional mechanisms that control PUMA protein stability are not understood. We show that a lysosome-independent activity of chloroquine (CQ) prevents degradation of PUMA protein, promotes apoptosis, and reduces the growth of melanoma xenografts in mice. Compared with wild-type PUMA, a BH3 domain-deleted PUMA protein showed impaired decay in melanoma cells. Fusion of the BH3 domain to a heterologous protein led to its rapid turnover that was inhibited by CQ. Although both CQ and inhibitors of lysosomal proteases stalled autophagy, only CQ stabilized PUMA protein and promoted apoptosis. Our results reveal a lysosomal protease-independent activity of CQ that selectively promotes apoptosis in melanoma cells.

Original languageEnglish (US)
Pages (from-to)2247-2254
Number of pages8
JournalJournal of Investigative Dermatology
Volume133
Issue number9
DOIs
StatePublished - Sep 2013

Fingerprint

Chloroquine
Modulators
Melanoma
Apoptosis
Degradation
Proteins
Peptide Hydrolases
Apoptosis Regulatory Proteins
Protein Stability
Autophagy
Lysosomes
Protease Inhibitors
Heterografts
Fusion reactions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Chloroquine promotes apoptosis in melanoma cells by inhibiting BH3 domain-mediated PUMA degradation. / Lakhter, Alexander J.; Sahu, Ravi P.; Sun, Yang; Kaufmann, William K.; Androphy, Elliot J.; Travers, Jeffrey B.; Naidu, Samisubbu R.

In: Journal of Investigative Dermatology, Vol. 133, No. 9, 09.2013, p. 2247-2254.

Research output: Contribution to journalArticle

Lakhter, Alexander J. ; Sahu, Ravi P. ; Sun, Yang ; Kaufmann, William K. ; Androphy, Elliot J. ; Travers, Jeffrey B. ; Naidu, Samisubbu R. / Chloroquine promotes apoptosis in melanoma cells by inhibiting BH3 domain-mediated PUMA degradation. In: Journal of Investigative Dermatology. 2013 ; Vol. 133, No. 9. pp. 2247-2254.
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