Abstract
Upregulation of IAPP drives metabolic reprogramming and p53-deficient tumor regression.
Major finding: Upregulation of IAPP drives metabolic reprogramming and p53-deficient tumor regression.
Mechanism: IAPP (also known as amylin) inhibits glycolysis and induces ROS and apoptosis via CALCR and RAMP3.
Impact: A synthetic analogue of amylin may represent a therapeutic strategy for p53-deficient cancers.
Loss or mutation of the tumor suppressor p53 is one of the most common genetic alterations in human cancer. Restoration of wild-type p53 function has been shown to effectively suppress tumor growth in mice, but has proven difficult to achieve in patients. Venkatanarayan and colleagues found that manipulation of the p53 family members p63 and p73 in the context of p53 deficiency reactivated tumor-suppressive signaling pathways to promote tumor regression. Conditional knockout of the dominant-negative isoforms of p63 (ΔNp63) or p73 (ΔNp73) in Trp53-null mice significantly reduced thymic lymphoma growth via induction of apoptosis and senescence and extended tumor-free survival. This tumor-suppressive effect was associated with upregulation of the acidic transactivation domain–bearing (TA) isoforms of p63 and p73. RNA sequencing analysis of ΔNp63- and ΔNp73-deficient thymic lymphomas revealed increased expression of several genes involved in metabolic regulation, in particular islet amyloid polypeptide (IAPP), which encodes amylin and was transcriptionally regulated by TAp63 and TAp73. Expression of IAPPresulted in a reduced rate of glycolysis and increased reactive oxygen species (ROS) and apoptosis in both murine and human p53-deficient cancer cells, and induced tumor regression of p53-deficient thymic lymphomas in mice. Similarly, treatment with pramlintide, a synthetic amylin analogue, inhibited glycolysis and resulted in rapid tumor regression. Mechanistically, secreted amylin suppressed p53-deficient tumor growth via interaction with the calcitonin receptor (CALCR) and receptor activity modifying protein 3 (RAMP3), as depletion or inhibition of either receptor ablated the antitumor effects of increased IAPP in vitro and in vivo. Furthermore, coexpression of IAPP, CALCR, and RAMP3 correlated with improved survival in several cancer types. These data identify IAPP as a tumor suppressor gene and provide preclinical evidence that pharmacologic induction of amylin-driven metabolic reprogramming may be an effective therapeutic strategy in p53-deficient cancers.
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