Chloroquine Promotes Apoptosis in Melanoma Cells by Inhibiting BH3 Domain-mediated PUMA Degradation

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2013 Feb 2

PMID 23370537

Citations 31

Authors

Alexander J Lakhter

Ravi P Sahu

Yang Sun

William K Kaufmann

Elliot J Androphy

Jeffrey B Travers

Samisubbu R Naidu

Affiliations

Soon will be listed here.

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.

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