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Author(s): Avinashnarayan Venkatanarayan [sup.1] [sup.2] [sup.3] [sup.4] , Payal Raulji [sup.1] [sup.2] , William Norton [sup.5] , Deepavali Chakravarti [sup.1] [sup.2] [sup.3] [sup.4] , Cristian Coarfa [sup.6] , Xiaohua Su [...], p53 is often mutated or lost in cancer; here inactivation of [DELTA]Np63 and [DELTA]Np73 in the absence of p53 is shown to result in metabolic reprogramming and tumour regression via activation of IAPP (islet amyloid polypeptide or amylin), and IAPP-based anti-diabetes therapeutic strategies show potential for the treatment of p53-deficient and mutant tumours. A novel approach to targeting p53 cancers The tumour suppressor p53 is often mutated or lost in cancer. There is evidence from mouse models that reactivation of p53 activity in tumours can result in regression, but direct reactivation of normal p53 activity has not developed into an effective strategy for treating human cancer. In this paper Elsa Flores and colleagues show in mice that inactivation of the p53 family proteins p63 and p73, in the absence of p53, results in metabolic reprogramming and tumour regression through the activation of IAPP (islet amyloid polypeptide, also known as amylin). The anti-diabetic drug pramlintide, an amylin analogue, caused tumour regression in mice with p53-deficient thymic lymphomas, suggesting a novel strategy that might be used to target p53-deficient cancers. TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice.sup.1,2 (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the [DELTA]N isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions.sup.3,4,5,6,7,8. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy.sup.9,10,11,12,13,14, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the [DELTA]N isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the [beta] cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.

The role of transcription factor, nuclear factor [erythroid-derived 2]-like 2 (Nrf2), is detoxification of xenobiotics, overcoming oxidative stress and offering resistance to ionizing radiation induced cell death. However, the role of Nrf2 in cancer progression remains debatable. Activation of Nrf2 dependent proteins is crucial in maintaining cellular redox homeostasis and combating toxicity of carcinogens. Thus, employing natural or synthetic activators of Nrf2 pathway is a promising approach for development of chemopreventive modalities. Intriguingly, recent reports have highlighted the dark side of Nrf2 suggesting that multiple cancer cells demonstrate constitutive activation of Nrf2 caused by mutations in Nrf2 or Keap-1 proteins, offering survival advantage. Additionally, Nrf2 pathway is also up-regulated in chemoresistant cells and may be a major contributor in acquired chemoresistance. Thus, targeting Nrf2 pathway has emerged as a novel strategy to improve efficacy of chemotherapeutic drugs. This review discusses the dark and bright sides of this transcription factor in line with the recent literature. [ABSTRACT FROM AUTHOR]