ABSTRACT
Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.
ABSTRACT
Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer.
Subject(s)
Phenylthiohydantoin , Prostatic Neoplasms , beta-Galactoside alpha-2,3-Sialyltransferase , Male , Humans , Prostatic Neoplasms/drug therapy , Benzamides/pharmacology , Nitriles , LigandsABSTRACT
The reactivation of developmental genes and pathways during adulthood may contribute to pathogenesis of diseases such as prostate cancer. Analysis of the mechanistic links between development and disease could be exploited to identify signalling pathways leading to disease in the prostate. However, the mechanisms underpinning prostate development require further characterisation to interrogate fully the link between development and disease. Previously, our group developed methods to produce prostate organoids using induced pluripotent stem cells (iPSCs). Here, we show that human iPSCs can be differentiated into prostate organoids using neonatal rat seminal vesicle mesenchyme in vitro. The organoids can be used to study prostate development or modified to study prostate cancer. We also elucidated molecular drivers of prostate induction through RNA-sequencing analyses of the rat urogenital sinus and neonatal seminal vesicles. We identified candidate drivers of prostate development evident in the inductive mesenchyme and epithelium involved with prostate specification. Our top candidates included Spx, Trib3, Snai1, Snai2, Nrg2 and Lrp4. This work lays the foundations for further interrogation of the reactivation of developmental genes in adulthood, leading to prostate disease.
Subject(s)
Induced Pluripotent Stem Cells , Prostatic Neoplasms , Male , Humans , Rats , Animals , Prostate , Rodentia , Urogenital System/physiology , Cell Differentiation/genetics , OrganoidsABSTRACT
Myostatin deficiency leads to both an increased rate of protein synthesis and skeletal muscle hypertrophy. However, the mechanisms involved in mediating these effects are not yet fully understood. Here, we demonstrate that genetic loss of myostatin leads to enhanced muscle expression of both protein kinase B and mammalian target of rapamycin/S6K signalling components, consistent with their elevated activity. This is associated with a reduction in the expression of PGC1alpha and COX IV, proteins which play important roles in maintaining mitochondrial function. Furthermore, we show that these changes in signalling and protein expression are largely independent of alterations in intramuscular amino acid content. Our findings, therefore, reveal potential new mechanisms and further contribute to our understanding of myostatin-regulated skeletal muscle growth and function.
Subject(s)
Muscle Development/genetics , Muscle, Skeletal/metabolism , Signal Transduction/genetics , Sirolimus/metabolism , Animals , Hypertrophy/metabolism , Mammals/genetics , Mammals/metabolism , Mice , Myostatin , Protein Biosynthesis , Proteins/genetics , Proteins/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolismABSTRACT
A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Amides/therapeutic use , Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Amides/pharmacology , Anti-Asthmatic Agents/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4 , Humans , Phosphodiesterase Inhibitors/pharmacologyABSTRACT
The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Area Under Curve , Cyclic Nucleotide Phosphodiesterases, Type 4 , Guinea Pigs , Phosphodiesterase Inhibitors/pharmacokinetics , Quinolines/pharmacokinetics , Vomiting/chemically inducedABSTRACT
The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).
Subject(s)
3',5'-Cyclic-AMP Phosphodiesterases/antagonists & inhibitors , Cyclic N-Oxides/chemical synthesis , Cyclic N-Oxides/pharmacology , Phosphodiesterase Inhibitors/chemical synthesis , Phosphodiesterase Inhibitors/pharmacology , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Area Under Curve , Cyclic N-Oxides/pharmacokinetics , Cyclic Nucleotide Phosphodiesterases, Type 4 , Guinea Pigs , Phosphodiesterase Inhibitors/pharmacokinetics , Quinolines/pharmacokineticsABSTRACT
The synthesis and pharmacological profile of a novel series of 7-methoxy-furo[2,3-c]pyridine-4-carboxamides is described. Some of these compounds were found to be potent inhibitors of phosphodiesterase type 4 (PDE4).