IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo
| Autor: | Payal Raulji, Preethi H. Gunaratne, Katherine A. Naff, Jaehyuk Lee, James A. Bankson, Kimal Rajapakshe, Cristian Coarfa, Charles V. Kingsley, Eliot Fletcher Sananikone, Jan Parker-Thornburg, William Norton, Elsa R. Flores, Santosh K. Sandur, Deepavali Chakravarti, Avinashnarayan Venkatanarayan, Marc S. Ramirez, Kenneth Y. Tsai, Xiaohua Su |
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| Rok vydání: | 2014 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Lymphoma Amyloid Amylin Thymus Gland Biology Receptor Activity-Modifying Protein 3 Article Mice Transactivation Downregulation and upregulation Cell Line Tumor Internal medicine medicine Animals Humans Genes Tumor Suppressor Calcitonin receptor Receptor Multidisciplinary Tumor Suppressor Proteins Nuclear Proteins Cancer Tumor Protein p73 Receptors Calcitonin Phosphoproteins medicine.disease Pramlintide Islet Amyloid Polypeptide 3. Good health DNA-Binding Proteins Cell Transformation Neoplastic Endocrinology Trans-Activators Cancer research Female Tumor Suppressor Protein p53 medicine.drug |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature13910 |
| Popis: | p53 is often mutated or lost in cancer; here inactivation of ΔNp63 and ΔNp73 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. 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 mice1,2 (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 ΔN 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 functions3,4,5,6,7,8. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy9,10,11,12,13,14, 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 ΔN 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 β 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. |
| Databáze: | OpenAIRE |
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