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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
IAPP-driven metabolic reprogramming induces regression of p53-deficient tumours in vivo
Avinashnarayan Venkatanarayan1, Payal Raulji2, William Norton3
11] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [4] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
Abstract:
TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (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 functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, 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.
Insights
Targeting p53 family members p63 and p73 offers a new strategy for treating p53-deficient cancers. Deleting specific p63/p73 forms triggers tumor regression by upregulating amylin, a peptide that inhibits tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Reprogramming
Background:
- TP53 gene alterations are common in human cancers, and reactivating p53 shows tumor-suppressive potential.
- The p53 family members, p63 and p73, have isoforms (TA and ΔN) with distinct roles in tumor suppression and oncogenesis.
- ΔN isoforms of p63 and p73 are frequently overexpressed in cancer, acting in a dominant-negative manner against tumor suppressive functions.
Purpose of the Study:
- To investigate targeting p53 family members (p63 and p73) as an alternative therapeutic strategy for p53-deficient cancers.
- To understand the interplay of the p53 family in cancer and its impact on tumor suppression.
- To explore the therapeutic potential of manipulating p63/p73 isoforms in p53-altered tumors.
Main Methods:
- Examined the effects of deleting ΔN isoforms of p63 or p73 in p53-deficient mouse models.
- Investigated the role of IAPP (amylin) in tumor regression.
- Analyzed the mechanism of amylin action via calcitonin receptor (CalcR) and RAMP3.
- Tested the efficacy of pramlintide, an amylin analogue, in p53-deficient thymic lymphomas.
Main Results:
- Deletion of ΔN isoforms of p63 or p73 led to metabolic reprogramming and regression of p53-deficient tumors.
- Upregulation of IAPP (amylin) was identified as a key factor in tumor regression.
- Amylin was found to inhibit glycolysis, induce reactive oxygen species, and promote apoptosis via CalcR/RAMP3.
- Pramlintide treatment resulted in rapid regression of p53-deficient thymic lymphomas.
Conclusions:
- Targeting p53 family members, specifically by deleting ΔN isoforms of p63 or p73, can induce regression of p53-deficient tumors.
- Amylin, upregulated by this manipulation, plays a causal role in tumor suppression through metabolic and apoptotic pathways.
- Pramlintide represents a novel therapeutic strategy for targeting p53-deficient cancers by mimicking amylin's tumor-suppressive effects.
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