Cancer is a complex disease where cancer stem cells (CSCs) maintain unlimited replicative potential, but evade chemotherapy drugs through cellular quiescence. CSCs are able to give rise to bulk tumor cells that have the capability to override anti-proliferative signals and evade apoptosis. Numerous pathways are dysregulated in tumor cells, where increased levels of pro-oxidant reactive oxygen and nitrogen species (RONS) can lead to localized inflammation to exacerbate all three stages of tumorigenesis: initiation, progression, and metastasis. Modulation of cellular metabolism in tumor cells as well as immune cells in the tumor microenvironment (TME) can impact inflammatory networks. Altering these pathways can potentially serve as a portal for therapy. It is well known that selenium, through selenoproteins, modulates inflammatory pathways in addition to regulating redox homeostasis in cells. Therefore, selenium has the potential to impact the interaction between tumor cells, cancer stem cells, and immune cells. In the sections below, we review the current status of knowledge regarding this interaction, with reference to leukemia stem cells (LSCs), and the importance of selenium-dependent regulation of inflammation as a potential mechanism to affect the TME and tumor cell survival.
Macrophages use various cell-surface receptors to sense their environment and undergo polarized responses. The cytokines, interleukin (IL)-4 and IL-13, released from T-helper type 2 (Th2) cells, drive macrophage polarization toward an alternatively activated phenotype (M2). This phenotype is associated with the expression of potent pro-resolving mediators, such as the prostaglandin (PG) D 2-derived cyclopentenone metabolite, 15d-PGJ 2 , produced by the cyclooxygenase (Ptgs; Cox) pathway. Interestingly, IL-4 treatment of bone marrow-derived macrophages (BMDMs) significantly down-regulates Cox-2 protein expression, whereas Cox-1 levels are significantly increased. This phenomenon not only challenges the dogma that Cox-1 is only developmentally regulated, but also demonstrates a novel mechanism in which IL-4-dependent regulation of Cox-1 involves the activation of the mechanistic target of rapamycin complex (mTORC). Using specific chemical inhibitors, we demonstrate here that IL-4-dependent Cox-1 up-regulation occurs at the post-transcriptional level via the Fes-Akt-mTORC axis. Activation of AMP-activated protein kinase (AMPK) by metformin, inhibition of mTORC by torin 1, or CRISPR/Cas9-mediated genetic knockout of tuberous sclerosis complex-2 (Tsc2) blocked the IL-4-dependent expression of Cox-1 and the ability of macrophages to polarize to M2. However, use of 15d-PGJ 2 partially rescued the effects of AMPK activation, suggesting the importance of Cox-1 in macrophage polarization as also observed in a model of gastrointestinal helminth clearance. In summary, these findings suggest a new paradigm where IL-4-dependent up-regulation of Cox-1 expression may play a key role in tissue homeostasis and wound healing during Th2-mediated immune responses, such as parasitic infections.
Prostaglandin D2 and its cyclopentenone metabolites [cyclopentenone prostaglandins (CyPGs)], Δ12prostaglandin J2 and 15‐deoxy‐Δ12, 14‐prostaglandin J2, act through2GPCRs, d‐type prostanoid 1 and the chemoattractant receptor homologous molecule expressed on type 2 T‐helper cells (Crth2). In addition to its role in allergy and asthma, the role of Crth2 in the resolution of inflammation, to mediate the proresolving functions of endogenous CyPGs, is not well understood. We investigated the regulation of LPS or zymosan‐induced inflammatory response by signals from the Crth2 receptor in macrophages that lack Crth2 expression [knockout (KO)]. Increased expression of proinflammatory genes, including Tnf‐α, was observed in Crth2 KO cells. Targeting the endogenous biosynthetic pathway of CyPGs with indomethacin or HQL79, which inhibit cyclooxygenases or hematopoietic prostaglandin D synthase, respectively, or use of Crth2 antagonists recapitulated the proinflammatory phenotype as in Crth2 KO cells. Ligand‐dependent activation of Crth2 by 13, 14‐dihydro‐15‐keto‐prostaglandin D2 increased Ca2+ influx through store‐operated Ca2+ entry (SOCE) accompanied by the up‐regulation of stromal interaction molecule 1 and calcium release‐activated calcium modulator 1 expression, suggesting that the proresolution effects of CyPG‐dependent activation of SOCE could be mediated by Crth2 during inflammation. Interestingly, Crth2 signaling down‐regulated the Ca2+‐regulated heat stable protein 1 that stabilizes Tnf‐α mRNA via the increased expression of microRNA 155 to dampen inflammatory responses triggered through the TNF‐α‐NF‐αB axis. In summary, these studies present a novel regulatory role for Crth2 during inflammatory response in macrophages.—Diwakar, B. T., Yoast, R., Nettleford, S., Qian, F., Lee, T.‐J., Berry, S., Huffnagle, I., Rossi, R. M., Trebak, M., Paulson, R. F., Prabhu, K. S. Crth2 receptor signaling down‐regulates lipopolysaccharide‐induced NF‐αB activation in murine macrophages via changes in intracellular calcium. FASEB J. 33, 12838–12852 (2019). http://www.fasebj.org
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