11 research outputs found
PI3Kα inhibition reduces obesity in mice
Partial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. The best known health beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have previously shown that a dual chemical inhibitor of the alpha and delta PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment. Here, we dissect the role of the alpha and delta PI3K isoforms by making use of selective inhibitors against PI3Kα (BYL-719 also known as alpelisib) or PI3Kδ (GS-9820 also known as acalisib). Treatment of mice with the above mentioned inhibitors indicated that BYL-719 increases energy expenditure in normal mice and efficiently reduces body weight in obese (ob/ob) mice, whereas these effects were not observed with GS-9820. Of note, the dose of BYL-719 required to reduce obesity was 10x higher than the equivalent dose of CNIO-PI3Ki, which could suggest that simultaneous inhibition of PI3K alpha and delta is more beneficial than single inhibition of the alpha isoform. In summary, we conclude that inhibition of PI3Kα is sufficient to increase energy expenditure and reduce obesity, and suggest that concomitant PI3Kα inhibition could play an auxiliary role
p21(Cip1) plays a critical role in the physiological adaptation to fasting through activation of PPARα.
Fasting is a physiological stress that elicits well-known metabolic adaptations, however, little is known about the role of stress-responsive tumor suppressors in fasting. Here, we have examined the expression of several tumor suppressors upon fasting in mice. Interestingly, p21 mRNA is uniquely induced in all the tissues tested, particularly in liver and muscle (>10 fold), and this upregulation is independent of p53. Remarkably, in contrast to wild-type mice, p21-null mice become severely morbid after prolonged fasting. The defective adaptation to fasting of p21-null mice is associated to elevated energy expenditure, accelerated depletion of fat stores, and premature activation of protein catabolism in the muscle. Analysis of the liver transcriptome and cell-based assays revealed that the absence of p21 partially impairs the transcriptional program of PPARα, a key regulator of fasting metabolism. Finally, treatment of p21-null mice with a PPARα agonist substantially protects them from their accelerated loss of fat upon fasting. We conclude that p21 plays a relevant role in fasting adaptation through the positive regulation of PPARα
A small-molecule PI3Kα activator for cardioprotection and neuroregeneration
Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1,2,3,4,5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development
Beta 1-integrin-c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes
This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this
article are included in the article’s Creative Commons license, unless indicated otherwise
in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material.
To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/R.B.M. was a recipient of a UK Medical Research Council (MRC) studentship, MRC
Centenary Award, Barts and The London Charity (472/1711) and Rosetrees Trust
(M314), N.K. was a recipient of an MRC studentship (MR/J500409/1), C.J. was a recipient
of the Barts and The London Charitable Foundation Scholarship (RAB 05/PJ/07),
L.M. was supported by CR-UK, Breast Cancer Now (2008NovPR10) and Rosetrees Trust
(M346), A.H. was a recipient of a CR-UK studentship (C236/A11795). P.J.P. was
supported by CR-UK. J.I. was supported by grants from the Academy of Finland, ERC
Starting grant, Finnish Cancer Organisations and Sigrid Juselius Foundation. S.K. was
supported by the MRC (G0501003) and The British Lung Foundation (CAN09-4)
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Intermittent PI3Ko inhibition sustains anti-tumor immunity and curbs irAEs
YesPhosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors
that target this PI3K have been approved for treatment of B cell malignancies1–3.
Although studies in mouse models of solid tumours have demonstrated that PI3Kδ
inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in
humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in
human patients with head and neck cancer in a neoadjuvant, double-blind,
placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ
inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and
enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses
of AMG319, immune-related adverse events (irAEs) required treatment to be
discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic
effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of
Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis
revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied
by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells,
which probably contributed to toxicity; this points towards a specific mode of action
for the emergence of irAEs. A modified treatment regimen with intermittent dosing of
PI3Kδi in mouse models led to a significant decrease in tumour growth without
inducing pathogenic T cells in colonic tissue, indicating that alternative dosing
regimens might limit toxicity