Targeting lysosomal degradation induces p53-dependent cell death and prevents cancer in mouse models of lymphomagenesis

Maclean, K.H. et al. J. Clin. Invest. 118, 79-88 (2008)

Speaker: 盧怡恬                                         Time: 14:10~15:00, Apr. 16, 2008

Commentator: 林秋烽 老師                                Place: Room 601

Abstract:

        Tumorgenesis is a multi-stage process that involves the activation of oncogenes as well as the inactivation of tumor suppressor pathway such as Atm-p53 pathway. P53 is a suppressor of tumorgenesis which can respond to many signals that stress the cell, including DNA damage. Previous studies indicate that loss of either Atm or p53 augments Myc-induced lymphomagenesis.^1,2 Chloroquine (CQ) is an antimalarial drug which can activate Atm and p53 without damaging DNA.³ In this study, the authors investigated the effect of CQ on the Myc-induced lymphoma development. They found that CQ prevented Myc-induced lymphomagenesis. They also observed that CQ induced cell death was dependent on p53, but not p53 modulators Atm or Arf, in many different cell types. In addition, after CQ treatment, markers of both apoptosis and autophagy were increased. Interestingly, CQ was effective at killing Myc-overexpressing cells even in lacking of Bax and Bak or overexpression of Bcl-2 or Bcl-X_L. Moreover, CQ induced markers of autophagy and disrupted the end-stage of autophagy, namely lysosomal protein degradation. However, if both apoptosis and autophagy were blocked, CQ could no longer effectively kill Myc-overexpressing cells. Thus CQ disrupts lysosomal function and induces a p53-dependent cell death that does not require caspase-mediated apoptosis.

References:

1.          Eischen, C.M. et al. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658–2669 (1999).

2.          Maclean, K.H. et al. Atm deficiency affects both apoptosis and proliferation to augment Myc-induced lymphomagenesis. Mol. Cancer Res. 5, 705–711 (2007).

3.          Bakkenist, C.J. and Kastan, M.B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 421, 499–506 (2003).