Ataxia Telangiectasia-Mutated and p53 Are Potential Mediators of Chloroquine-Induced Resistance to Mammary Carcinogenesis

Abstract

The use of agents to prevent the onset of and/or the progression to breast cancer has the potential to lower breast cancer risk. We have previously shown that the tumor-suppressor gene p53 is a potential mediator of hormone (estrogen/progesterone)-induced protection against chemical carcinogen-induced mammary carcinogenesis in animal models. Here, we show for the first time a breast cancer-protective effect of chloroquine in an animal model. Chloroquine significantly reduced the incidence of N-methyl-N-nitrosourea-induced mammary tumors in our animal model similar to estrogen/progesterone treatment. No protection was seen in our BALB/c p53-null mammary epithelium model, indicating a p53 dependency for the chloroquine effect. Using a human nontumorigenic mammary gland epithelial cell line, MCF10A, we confirm that in the absence of detectable DNA damage, chloroquine activates the tumor-suppressor p53 and the p53 downstream target gene p21, resulting in G 1 cell cycle arrest. p53 activation occurs at a posttranslational level via chloroquine-dependent phosphorylation of the checkpoint protein kinase, ataxia telangiectasia-mutated (ATM), leading to ATM-dependent phosphorylation of p53. In primary mammary gland epithelial cells isolated from p53-null mice, chloroquine does not induce G 1 cell cycle arrest compared with cells isolated from wildtype mice, also indicating a p53 dependency. Our results indicate that a short prior exposure to chloroquine may have a preventative application for mammary carcinogenesis.

Chromatin modifying protein 1A (Chmp1A) of the endosomal sorting complex required for transport (ESCRT)-III family activates ataxia telangiectasia mutated (ATM) for PanC-1 cell growth inhibition

“…42 ATM also participates in cellular pathways that are not directly linked to DNA damage. Inhibitors of histone deacetylases (HDACs), such as trichostatin A or chloroquine were shown to activate ATM kinase activity independently of DNA damage, 43 indicating the significance ©2 0 1 1 L a n d e s B i o s c i e n c e .…”

“…3D). Since serine 15 of p53 is a substrate for ATM kinase, 43 Chmp1A-mediated activation of ATM could potentially lead to p53 phosphorylation. To examine this, we performed in vitro ATM kinase assays using recombinant p53 protein (rp53) as substrate and measured the phosphorylation level of rp53 at S15.…”

p53 is required for chloroquine-induced atheroprotection but not insulin sensitization

“…The notion of modulating the genotoxic stress response through the use of chloroquine to activate ATM ( 26 ) has been proposed as a therapeutic strategy in some forms of cancer ( 44,45 ). Such an approach is logical because cancer is a disease characterized by abnormal DNA.…”

Selenite triggers rapid transcriptional activation of p53, and p53-mediated apoptosis in prostate cancer cells: Implication for the treatment of early-stage prostate cancer

“…Recently, DNAdamage independent activation of ATM kinase and phosphorylation of p53 at serine-15 has been observed upon treatment with chloroquine and indole-3-carbinol (41,42). Thus, we wanted to know whether DNA double strand breaks occur in LNCaP cells upon treatment with selenite.…”