Restoration of p53 functions protects cells from concanavalin A-induced apoptosis.

Department of Genetics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Molecular Cancer Therapeutics (Impact Factor: 5.6). 02/2010; 9(2):471-9. DOI: 10.1158/1535-7163.MCT-09-0732
Source: PubMed

ABSTRACT A great majority of human cancers encounter disruption of the p53 network. Identification and characterization of molecular components important in both p53-dependent and p53-independent apoptosis might be useful in developing novel therapies. Previously, we reported that concanavalin A (Con A) induced p73-dependent apoptosis of cells lacking functional p53. In the present study, we investigated the mechanism and role of p53 in protection from apoptosis induced by Con A. Treatment with Con A resulted in apoptosis of p53-null ovarian cancer, SKOV3, or Li-Fraumeni syndrome, MDAH041 (041), cells. However, their isogenic pairs, SKP53 and TR9-7, expressing wild-type p53 were much less sensitive and were protected by G(1) arrest. Inhibition of p53 function rendered these cells sensitive to Con A. Con A-induced apoptosis was accompanied by upregulation of forkhead box O1a (FOXO1a) and Bcl-2-interacting mediator (Bim), which were strongly inhibited after p53 expression and rescued after p53 ablation. Moreover, ablation of Bim by short hairpin RNA protected cells from apoptosis. Taken together, our study suggests that Con A induces apoptosis of cells lacking p53 by activating FOXO1a-Bim signaling and that expression of p53 protects these cells by inducing G(1) arrest and by downregulating the expression of both FOXO1a and Bim, identifying a novel cross-talk between FOXO1a and p53 transcription factors.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Most patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) undergo definitive therapy, yet locoregional recurrence and metastasis are common. Most patients ultimately require systemic treatment. Platinum/5-fluorouracil (5-FU) has been the standard of care for patients with good performance status (median survival, 6-8 months). Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), significantly improved median survival in combination with platinum/5-FU compared with chemotherapy alone, establishing it as a new standard for patients with recurrent or metastatic disease. Cetuximab is also active in platinum-refractory disease. Ongoing trials are exploring other EGFR inhibitors as well as the use of biologic agents in combination (eg, cetuximab + bevacizumab). Predictive biomarkers may help personalize therapy for SCCHN, and it is unclear whether the favorable prognostic effect of p16 or human papillomavirus in locally advanced oropharyngeal cancer is relevant for advanced disease. Head Neck, 2011.
    Head & Neck 11/2011; · 2.83 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: p53 is essential for the cellular responses to DNA damage that help to maintain genomic stability. However, the great majority of human cancers undergo disruption of the p53-network. Identification and characterization of molecular components important in both p53-dependent and -independent apoptosis might be useful in developing novel therapies for cancers. In the complete absence of p53, cells treated with N-(phosphonacetyl)-L-aspartate (PALA) continue to synthesize DNA slowly and eventually progress through S-phase, suffering severe DNA damage that in turn triggers apoptosis, whereas cells with functional p53 undergo growth arrest. In this study, we investigated apoptotic signaling in response to PALA and the role of p53 expression in this pathway. We found that treatment of cells lacking p53 with PALA induced TAp73, Noxa and Bim and inactivation of these proteins with dominant-negative plasmids or small interfering RNAs significantly inhibited apoptosis, suggesting that PALA-induced apoptosis was mediated via TAp73-dependent expression of Noxa and Bim. However, PALA treatment inhibited the expression of ΔNp73 only in cells lacking p53 but not in cells expressing p53. In addition, PALA treatment inhibited Bcl-2, and overexpression of Bcl-2 significantly inhibited PALA-induced apoptosis. Moreover, expression of p53 in these cells protected them from PALA-induced apoptosis by activating p21, sustaining the expression of ΔNp73 and inhibiting the induction of Noxa and Bim. Taken together, our study identifies novel but opposing roles for the p53 and TAp73 in the induction of Noxa and Bim and regulation of apoptosis. Our data will help to develop strategies to eliminate cancer cells lacking p53 while protecting normal cells with wild-type p53.Oncogene advance online publication, 19 March 2012; doi:10.1038/onc.2012.96.
    Oncogene 03/2012; · 8.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our previous study has shown that activation of JNK plays a critical role in Porcine reproductive and respiratory syndrome virus (PRRSV)-mediated apoptosis. In this follow-up study, we further investigated the mechanisms involved in modulation of PRRSV-mediated JNK activation and apoptosis. We found that unfolded protein response (UPR) was induced in response to PRRSV infection which in turn triggered JNK activation and apoptosis. We also found that p53 and Akt were activated at the early stage of infection and functioned as negative regulator of JNK activation to counteract the PRRSV-mediated apoptosis. Furthermore, induction of UPR, p53 and Akt was not only involved in modulation of PRRSV-mediated apoptosis, but also contributed to the virus replication. Our findings indicated that multiple signaling pathways were involved in modulation of PRRSV-mediated apoptosis of the host cells via regulating JNK signaling pathway and provided novel insights into understanding the mechanisms of pathogenesis of PRRSV infection.
    Virology 07/2013; · 3.28 Impact Factor