Catechin pentaacetate

31515267

Ligand-dependent differences in the regulation and internalization of the μ-opioid receptor (MOR) have been linked to the severity of adverse effects that limit opiate use in pain management. MOR activation by morphine or [d-Ala2,N-MePhe4, Gly-ol]enkephalin (DAMGO) causes differences in spatiotemporal signaling dependent on MOR distribution at the plasma membrane. Morphine stimulation of MOR activates a Gαi/o-Gβγ-protein kinase C (PKC) α phosphorylation pathway that limits MOR distribution and is associated with a sustained increase in cytosolic extracellular signal-regulated kinase (ERK) activity. In contrast, DAMGO causes a redistribution of the MOR at the plasma membrane (before receptor internalization) that facilitates transient activation of cytosolic and nuclear ERK. Here, we used proximity biotinylation proteomics to dissect the different protein-interaction networks that underlie the spatiotemporal signaling of morphine and DAMGO. We found that DAMGO, but not morphine, activates Ras-related C3 botulinum toxin substrate 1 (Rac1). Both Rac1 and nuclear ERK activity depended on the scaffolding proteins IQ motif-containing GTPase-activating protein-1 (IQGAP1) and Crk-like (CRKL) protein. In contrast, morphine increased the proximity of the MOR to desmosomal proteins, which form specialized and highly-ordered membrane domains. Knockdown of two desmosomal proteins, junction plakoglobin or desmocolin-1, switched the morphine spatiotemporal signaling profile to mimic that of DAMGO, resulting in a transient increase in nuclear ERK activity. The identification of the MOR-interaction networks that control differential spatiotemporal signaling reported here is an important step toward understanding how signal compartmentalization contributes to opioid-induced responses, including anti-nociception and the development of tolerance and dependence.

G protein-coupled receptor (GPCR), opiate opioid, cell compartmentalization, protein complex, proteomics, extracellular signal-regulated kinase (ERK), desmosome, Ras-related C3 botulinum toxin substrate 1 (Rac1), cell signaling, opioid-based analgesics

Ligand-dependent spatiotemporal signaling profiles of the μ-opioid receptor are controlled by distinct protein-interaction networks

Srgjan Civciristov,‡ Cheng Huang,§¶ Bonan Liu,‡ Elsa A. Marquez,¶ Arisbel B. Gondin,‡ Ralf B. Schittenhelm,§¶ Andrew M. Ellisdon,¶ Meritxell Canals,‡,1 and Michelle L. Halls‡,2

2019 Nov 1;

25938544

Reprogramming energy metabolism, such as enhanced glycolysis, is an Achilles’ heel in cancer treatment. Most studies have been performed on isolated cancer cells. Here, we studied the energy-transfer mechanism in inflammatory tumor microenvironment. We found that human THP-1 monocytes took up lactate secreted from tumor cells through monocarboxylate transporter 1. In THP-1 monocytes, the oxidation product of lactate, pyruvate competed with the substrate of proline hydroxylase and inhibited its activity, resulting in the stabilization of HIF-1α under normoxia. Mechanistically, activated hypoxia-inducible factor 1-α in THP-1 monocytes promoted the transcriptions of prostaglandin-endoperoxide synthase 2 and phosphoenolpyruvate carboxykinase, which were the key enzyme of prostaglandin E2 synthesis and gluconeogenesis, respectively, and promote the growth of human colon cancer HCT116 cells. Interestingly, lactate could not accelerate the growth of colon cancer directly in vivo. Instead, the human monocytic cells affected by lactate would play critical roles to ‘feed’ the colon cancer cells. Thus, recycling of lactate for glucose regeneration was reported in cancer metabolism. The anabolic metabolism of monocytes in inflammatory tumor microenvironment may be a critical event during tumor development, allowing accelerated tumor growth.

lactate, HIF-1α, gluconeogenesis, inflammation, microenvironment

Lactate promotes PGE2 synthesis and gluconeogenesis in monocytes to benefit the growth of inflammation-associated colorectal tumor

Libin Wei,1 Yuxin Zhou,1 Jing Yao,1 Chen Qiao,1 Ting Ni,1 Ruichen Guo,2 Qinglong Guo,1 and Na Lu1

2015 Jun 30