The need to identify drugs and pathways that induce cell death independently of p53 deserves substantial attention. Induction of cancer cell death is challenging when p53 and other apoptotic pathways are inactivated, and requires chemotherapeutics that induce cell death pathways that do not require the tumor suppressor p53, as at least 50 percent of cancers lack a functional p53 pathway. We published that different mitomycins, which are alkylating agents, activate p53-dependent and p53-independent cell death. We see the mitomycin derivative 10-decarbamyl mitomycin C (DMC), as opposed to mitomycin C (MC), can rapidly activate a p53-independent cell death pathway which lacks markers of apoptotic death. DMC-induced cell death is a good model for identifying targets for the induction of p53-independent cell death pathways, such as necrosis and autophagy. Our central hypothesis is that DMC provokes p53-independent cell death due to specific DNA adducts formed and that elucidating the pathway(s) will enable efficient drug design parameters. Identifying the mechanisms by which DMC induces cell death is the focus of this proposal and will be a first step toward developing drugs to strategically induce cell death for the many cancers lacking functional p53 pathways. Despite the importance of p53-independent cell death, little is known about the activation of such pathways.
Four aims are proposed that will use a human cancer cell line with inducible p53 and its isogenic pair (without p53) to examine p53 dependency and independency in cell death signaling, and C. elegans to serve as a preclinical model system. (1) Identify the human signal transduction pathways required for cell death in the presence and absence of p53 that are activated and/or repressed by DMC and MC. (2) Analyze the ability of DMC and MC DNA adducts in vitro and in vivo to recruit DNA repair proteins in the presence and absence of p53. (3) Perform comparative analysis of the influence of the p53 pathway and the autophagy pathway on the chemotherapeutic DNA damage-induced cell death in C. elegans and human cell systems. (4) Obtain R01 funding for my laboratory research. There is a gap in knowledge as to how to target for p53-independent cell death. Knowledge of the signaling mechanisms for p53-independent cell death pathways will help in targeting drugs to patients who have cancers that lack functional p53.
|Xiao, Gu; Kue, Pao; Bhosle, Rahul et al. (2015) Decarbamoyl mitomycin C (DMC) activates p53-independent ataxia telangiectasia and rad3 related protein (ATR) chromatin eviction. Cell Cycle 14:744-54|
|Hoffman, Sandy; Martin, Daniel; Meléndez, Alicia et al. (2014) C. elegans CEP-1/p53 and BEC-1 are involved in DNA repair. PLoS One 9:e88828|
|Polotskaia, Alla; Hoffman, Sandy; Krett, Nancy L et al. (2012) 8-Amino-adenosine activates p53-independent cell death of metastatic breast cancers. Mol Cancer Ther 11:2495-504|
|Boamah, Ernest K; Brekman, Angelika; Tomasz, Maria et al. (2010) DNA adducts of decarbamoyl mitomycin C efficiently kill cells without wild-type p53 resulting from proteasome-mediated degradation of checkpoint protein 1. Chem Res Toxicol 23:1151-62|
|Bargonetti, Jill; Champeil, Elise; Tomasz, Maria (2010) Differential toxicity of DNA adducts of mitomycin C. J Nucleic Acids 2010:|