Cloroquina promove apoptose em células do melanoma
Chloroquine promotes apoptosis in melanoma cells by
inhibiting BH3 domain-mediated PUMA degradation.
Lakhter AJ, Sahu RP, Sun Y, Kaufmann WK, Androphy EJ, Travers JB, Naidu SR.
J Invest Dermatol. 2013 Sep;133(9):2247-54. doi: 10.1038/jid.2013.56. Epub 2013 Jan 31.
Source
Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, USA.
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.
PMID:23370537
PUMA: a puzzle piece in chloroquine's antimelanoma activity.
Amaravadi RK.
J Invest Dermatol. 2013 Sep;133(9):2133-5. doi: 10.1038/jid.2013.135.
Source
Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
[email protected]
Abstract
Chloroquine (CQ) can induce cell death in a subset of cancer cell lines, and some melanoma
cell lines are quite susceptible. Although it is well known that CQ impairs lysosomal function and
can serve as an autophagy inhibitor, the molecular target of CQ and the subsequent cascade of
events that lead to cell death are not fully understood. Recent evidence indicates that in
melanoma cell lines, CQ induces apoptosis by preventing degradation of the pro-apoptotic BH3only protein p53-upregulated modulator of apoptosis. This finding adds to the unfolding story of
CQ's mechanism of action as a cancer therapeutic agent.
Comment on
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Chloroquine promotes apoptosis in melanoma cells by inhibiting BH3 domain-mediated
PUMA degradation. [J Invest Dermatol. 2013]
PMID:
23949767