Signaling interplay between PARP1 and ROS regulates stress-induced cell death and developmental changes in Dictyostelium discoideum.

Poly (ADP-ribose) polymerase-1 (PARP1) is a DNA damage sensor that gets activated in proportion to the damage, helping cells to determine whether to repair the damage or initiate cell death processes. We have previously shown PARP1's significance in the developmental processes of Dictyostelium discoideum in addition to its role in oxidative stress and UV-C stress induced cell death. In this study, we show the significance of ROS in PARP1 mediated responses of D. discoideum under different stress conditions. Interestingly, our results suggest differential kinetics of PARP1 activation and implications of ROS in starvation and cadmium induced cell death events. Increased accumulation of Poly (ADP-ribose), a product of PARP activation, could be detected within minutes post cadmium stress, whereas PARP1 activation was only a later event with starvation. Starvation induced PARP1 activation was supported by the depletion of ATP and NAD+, while PARP inhibitor confers protective effect during starvation. During starvation, cell death is induced in two phases, a primary ROS driven PARP1 independent early necrotic phase followed by a PARP1 driven ROS dependent paraptotic phase; both of which comprise mitochondrial changes. Cadmium (Cd) exerted a dose-dependent effect on cell death; a low dose of 0.2 mM Cd led to paraptosis and a higher dose of 0.5 mM Cd led to necrosis in D. discoideum cells within 24 h. Interestingly, glutathione (GSH) exposure could rescue cells from Cd stress mediated cell death. Besides unicellular cell death, the developmental arrest induced by cadmium and oxidative stress could be rescued by reinstating the redox equilibrium using GSH. In conclusion, we underscore the significant link between PARP1 and ROS in regulating the process of cell death and development in D. discoideum.

CCL25 Signaling in the Tumor Microenvironment.

Multiple checkpoint mechanisms are overridden by cancer cells in order to develop into a tumor. Neoplastic cells, while constantly changing during the course of cancer progression, also craft their surroundings to meet their growing needs. This crafting involves changing cell surface receptors, affecting response to extracellular signals and secretion of signals that affect the nearby cells and extracellular matrix architecture. This chapter briefly comprehends the non-cancer cells facilitating the cancer growth and elaborates on the notable role of the CCR9-CCL25 chemokine axis in shaping the tumor microenvironment (TME), directly and via immune cells. Association of increased CCR9 and CCL25 levels in various tumors has demonstrated the significance of this axis as a tool commonly used by cancer to flourish. It is involved in attracting immune cells in the tumor and determining their fate via various direct and indirect mechanisms and, leaning the TME toward immunosuppressive state. Besides, elevated CCR9-CCL25 signaling allows survival and rapid proliferation of cancer cells in an otherwise repressive environment. It modulates the intra- and extracellular protein matrix to instigate tumor dissemination and creates a supportive metastatic niche at the secondary sites. Lastly, this chapter abridges the latest research efforts and challenges in using the CCR9-CCL25 axis as a cancer-specific target.

Phosphorylation hotspot in the C-terminal domain of occludin regulates the dynamics of epithelial junctional complexes.

The apical junctional complex (AJC), which includes tight junctions (TJs) and adherens junctions (AJs), determines the epithelial polarity, cell-cell adhesion and permeability barrier. An intriguing characteristic of a TJ is the dynamic nature of its multiprotein complex. Occludin is the most mobile TJ protein, but its significance in TJ dynamics is poorly understood. On the basis of phosphorylation sites, we distinguished a sequence in the C-terminal domain of occludin as a regulatory motif (ORM). Deletion of ORM and expression of a deletion mutant of occludin in renal and intestinal epithelia reduced the mobility of occludin at the TJs. ORM deletion attenuated Ca2+ depletion, osmotic stress and hydrogen peroxide-induced disruption of TJs, AJs and the cytoskeleton. The double point mutations T403A/T404A, but not T403D/T404D, in occludin mimicked the effects of ORM deletion on occludin mobility and AJC disruption by Ca2+ depletion. Both Y398A/Y402A and Y398D/Y402D double point mutations partially blocked AJC disruption. Expression of a deletion mutant of occludin attenuated collective cell migration in the renal and intestinal epithelia. Overall, this study reveals the role of ORM and its phosphorylation in occludin mobility, AJC dynamics and epithelial cell migration.

Emodin inhibits colon cancer by altering BCL-2 family proteins and cell survival pathways.

BACKGROUND: Currently offered therapeutics to treat colon cancer (CoCa) are toxic when given at maximum tolerated dose to achieve optimal clinical response. Hence, less toxic therapeutic intervention is needed to treat CoCa. In this study, we investigated the effect of a natural agent, Emodin, on CoCa. METHODS: Cell viability (MTT) assay was used to determine the effect of Emodin on human CoCa and colon epithelial cells. Flow cytometric analysis was used to determine Emodin induced cell death. Antibody microarray and western blot analyses were used to determine Emodin induced molecular changes involved in cell death. Change in mitochondrial membrane potential in response to Emodin was determined by flow cytometric analysis. Expression and localization of Bcl-2 family proteins were assessed by western blot analysis. RESULTS: Emodin decreased viability of CoCa cells and induced apoptosis in a time and dose-dependent manner compared to vehicle-treated control without significantly impacting normal colon epithelial cells. Emodin activated caspases, modulated Bcl-2 family of proteins and reduced mitochondrial membrane potential to induce CoCa cell death. Further, changes in Bcl-2 family protein expression and localization correlated with loss in mitochondrial membrane potential. Signaling (MAPK/JNK, PI3K/AKT, NF-κß and STAT) pathways associated with cell growth, differentiation, and Bcl-2 family expression or function were negatively regulated by Emodin. CONCLUSIONS: Ability of Emodin to impact molecular pathways involved in cell survival and apoptosis highlight the potential of this agent as a new and less toxic alternative for CoCa treatment.

Quercetin inhibits prostate cancer by attenuating cell survival and inhibiting anti-apoptotic pathways.

BACKGROUND: Despite recent advances in diagnosis and treatment, prostate cancer (PCa) remains the leading cause of cancer-related deaths in men. Current treatments offered in the clinics are often toxic and have severe side effects. Hence, to treat and manage PCa, new agents with fewer side effects or having potential to reduce side effects of conventional therapy are needed. In this study, we show anti-cancer effects of quercetin, an abundant bioflavonoid commonly used to treat prostatitis, and defined quercetin-induced cellular and molecular changes leading to PCa cell death. METHODS: Cell viability was assessed using MTT. Cell death mode, mitochondrial outer membrane potential, and oxidative stress levels were determined by flow cytometry using Annexin V-7 AAD dual staining kit, JC-1 dye, and ROS detection kit, respectively. Antibody microarray and western blot were used to delineate the molecular changes induced by quercetin. RESULTS: PCa cells treated with various concentrations of quercetin showed time- and dose-dependent decrease in cell viability compared to controls, without affecting normal prostate epithelial cells. Quercetin led to apoptotic and necrotic cell death in PCa cells by affecting the mitochondrial integrity and disturbing the ROS homeostasis depending upon the genetic makeup and oxidative status of the cells. LNCaP and PC-3 cells that have an oxidative cellular environment showed ROS quenching after quercetin treatment while DU-145 showed rise in ROS levels despite having a highly reductive environment. Opposing effects of quercetin were also observed on the pro-survival pathways of PCa cells. PCa cells with mutated p53 (DU-145) and increased ROS showed significant reduction in the activation of pro-survival Akt pathway while Raf/MEK were activated in response to quercetin. PC-3 cells lacking p53 and PTEN with reduced ROS levels showed significant activation of Akt and NF-κB pathway. Although some of these changes are commonly associated with oncogenic response, the cumulative effect of these alterations is PCa cell death. CONCLUSIONS: Our results demonstrated quercetin exerts its anti-cancer effects by modulating ROS, Akt, and NF-κB pathways. Quercetin could be used as a chemopreventive option as well as in combination with chemotherapeutic drugs to improve clinical outcomes of PCa patients.

Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice.

BACKGROUND: Disruption of epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia play crucial role in the pathogenesis of alcoholic tissue injury. Occludin, a transmembrane protein of TJ, is depleted in colon by alcohol. However, it is unknown whether occludin depletion influences alcoholic gut and liver injury. METHODS: Wild type (WT) and occludin deficient (Ocln(-/-)) mice were fed 1-6% ethanol in Lieber-DeCarli diet. Gut permeability was measured by vascular-to-luminal flux of FITC-inulin. Junctional integrity was analyzed by confocal microscopy. Liver injury was assessed by plasma transaminase, histopathology and triglyceride analyses. The effect of occludin depletion on acetaldehyde-induced TJ disruption was confirmed in Caco-2 cell monolayers. RESULTS: Ethanol feeding significantly reduced body weight gain in Ocln(-/-) mice. Ethanol increased inulin permeability in colon of both WT and Ocln(-/-) mice, but the effect was 4-fold higher in Ocln(-/-) mice. The gross morphology of colonic mucosa was unaltered, but ethanol disrupted the actin cytoskeleton, induced redistribution of occludin, ZO-1, E-cadherin and ß-catenin from the junctions and elevated TLR4, which was more severe in Ocln(-/-) mice. Occludin knockdown significantly enhanced acetaldehyde-induced TJ disruption and barrier dysfunction in Caco-2 cell monolayers. Ethanol significantly increased liver weight and plasma transaminase activity in Ocln(-/-) mice, but not in WT mice. Histological analysis indicated more severe lesions and fat deposition in the liver of ethanol-fed Ocln(-/-) mice. Ethanol-induced elevation of liver triglyceride was also higher in Ocln(-/-) mice. CONCLUSION: This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.

Potential role of Apoptosis Inducing Factor in evolutionarily significant eukaryote, Dictyostelium discoideum survival.

Apoptosis Inducing Factor (AIF), a phylogenetically conserved mitochondrial inter-membrane space flavoprotein has an important role in caspase independent cell death. Nevertheless, AIF is also essential for cell survival. It is required for mitochondrial organization and energy metabolism. Upon apoptotic stimulation, AIF induces DNA fragmentation after its mitochondrio-nuclear translocation. Although it executes critical cellular functions in a coordinated manner, the exact mechanism still remains obscure. The present study aims to understand AIF's role in cell survival, growth and development by its down-regulation in an interesting unicellular eukaryote, D. discoideum which exhibits multicellularity upon starvation. Constitutive AIF down-regulated (dR) cells exhibited slower growth and delayed developmental morphogenesis. Also, constitutive AIF dR cells manifested high intracellular ROS, oxidative DNA damage and calcium levels with lower ATP content. Interestingly, constitutive AIF dR cells showed amelioration in cell growth upon antioxidant treatment, strengthening its role as ROS regulator. Under oxidative stress, AIF dR cells showed early mitochondrial membrane depolarization followed by AIF translocation from mitochondria to nucleus and exhibited necrotic cell death as compared to paraptoptic cell death of control cells. Thus, the results of this study provide an exemplar where AIF is involved in growth and development by regulating ROS levels and maintaining mitochondrial function in D. discoideum, an evolutionarily significant model organism exhibiting caspase independent apoptosis.

CCR6 expression in colon cancer is associated with advanced disease and supports epithelial-to-mesenchymal transition.

BACKGROUND: Adjuvant chemotherapy offered to treat colon cancer is based on the TNM staging system, which often fails due to molecular heterogeneity and undefined molecular mechanisms independent of TNM. Therefore, identification of markers to better predict therapeutic option and outcome is needed. In this study we have characterised the clinical association of CCR6 with colon cancer and defined CCR6-mediated molecular pathway. METHODS: Immunohistochemistry, RT-qPCR, western blot and FACS were used to determine expression of CCR6 and/or EMT markers in colon tissues/cells. BrdU assay and trans-well system were used to determine cell proliferation, migration and invasion in response to CCL20. RESULTS: CCR6 was higher in cancer cases compared to normal adjacent tissue and expression was associated with nodal status and distant metastasis. Similarly, CCR6 expression was higher in cells derived from node-positive cases and highest expression was in cells derived from metastatic cases. Significant changes in EMT markers, that is, E-cadherin, vimentin, ß-catenin, N-cadherin, α-SMA, SNAILl and ZEB1 were observed in response to CCL20 along with decreased proliferation, increased migratory and invasive potential. CONCLUSIONS: Results suggest CCR6 as a potential therapeutic target as well as biomarker in addition to nodal status for predicting therapeutic option.

Chronic ethanol feeding promotes azoxymethane and dextran sulfate sodium-induced colonic tumorigenesis potentially by enhancing mucosal inflammation.

BACKGROUND: Alcohol consumption is one of the major risk factors for colorectal cancer. However, the mechanism involved in this effect of alcohol is unknown. METHODS: We evaluated the effect of chronic ethanol feeding on azoxymethane and dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in mouse colon. Inflammation in colonic mucosa was assessed at a precancerous stage by evaluating mucosal infiltration of neutrophils and macrophages, and analysis of cytokine and chemokine gene expression. RESULTS: Chronic ethanol feeding significantly increased the number and size of polyps in colon of AOM/DSS treated mice. Confocal microscopic and immunoblot analyses showed a significant elevation of phospho-Smad, VEGF and HIF1α in the colonic mucosa. RT-PCR analysis at a precancerous stage indicated that ethanol significantly increases the expression of cytokines IL-1α, IL-6 and TNFα, and the chemokines CCL5/RANTES, CXCL9/MIG and CXCL10/IP-10 in the colonic mucosa of AOM/DSS treated mice. Confocal microscopy showed that ethanol feeding induces a dramatic elevation of myeloperoxidase, Gr1 and CD68-positive cells in the colonic mucosa of AOM/DSS-treated mice. Ethanol feeding enhanced AOM/DSS-induced suppression of tight junction protein expression and elevated cell proliferation marker, Ki-67 in the colonic epithelium. CONCLUSION: This study demonstrates that chronic ethanol feeding promotes colonic tumorigenesis potentially by enhancing inflammation and elevation of proinflammatory cytokines and chemokines.

ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice.

BACKGROUND: Acetaldehyde, the toxic ethanol (EtOH) metabolite, disrupts intestinal epithelial barrier function. Aldehyde dehydrogenase (ALDH) detoxifies acetaldehyde into acetate. Subpopulations of Asians and Native Americans show polymorphism with loss-of-function mutations in ALDH2. We evaluated the effect of ALDH2 deficiency on EtOH-induced disruption of intestinal epithelial tight junctions and adherens junctions, gut barrier dysfunction, and liver injury. METHODS: Wild-type and ALDH2-deficient mice were fed EtOH (1 to 6%) in Lieber-DeCarli diet for 4 weeks. Gut permeability in vivo was measured by plasma-to-luminal flux of FITC-inulin, tight junction and adherens junction integrity was analyzed by confocal microscopy, and liver injury was assessed by the analysis of plasma transaminase activity, histopathology, and liver triglyceride. RESULTS: EtOH feeding elevated colonic mucosal acetaldehyde, which was significantly greater in ALDH2-deficient mice. ALDH2(-/-) mice showed a drastic reduction in the EtOH diet intake. Therefore, this study was continued only in wild-type and ALDH2(+/-) mice. EtOH feeding elevated mucosal inulin permeability in distal colon, but not in proximal colon, ileum, or jejunum of wild-type mice. In ALDH2(+/-) mice, EtOH-induced inulin permeability in distal colon was not only higher than that in wild-type mice, but inulin permeability was also elevated in the proximal colon, ileum, and jejunum. Greater inulin permeability in distal colon of ALDH2(+/-) mice was associated with a more severe redistribution of tight junction and adherens junction proteins from the intercellular junctions. In ALDH2(+/-) mice, but not in wild-type mice, EtOH feeding caused a loss of junctional distribution of tight junction and adherens junction proteins in the ileum. Histopathology, plasma transaminases, and liver triglyceride analyses showed that EtOH-induced liver damage was significantly greater in ALDH2(+/-) mice compared to wild-type mice. CONCLUSIONS: These data demonstrate that ALDH2 deficiency enhances EtOH-induced disruption of intestinal epithelial tight junctions, barrier dysfunction, and liver damage.

Mutations in the lipase-H gene causing autosomal recessive hypotrichosis and woolly hair.

Hypotrichosis is characterised by sparse scalp hair, sparse to absent eyebrows and eyelashes, or absence of hair from other parts of the body. In few cases, the condition is associated with tightly curled woolly scalp hair. The present study searched for disease-causing sequence variants in the genes in four Pakistani lineal consanguineous families exhibiting features of hypotrichosis or woolly hair. A haplotype analysis established links in all four families to the LIPH gene located on chromosome 3q27.2. Subsequently, sequencing LIPH identified a novel non-sense mutation (c.328C>T; p.Arg110*) in one and a previously reported 2-bp deletion mutation (c.659_660delTA, p.Ile220ArgfsX29) in three other families.

Involvement of poly(ADP-ribose) polymerase in paraptotic cell death of D. discoideum.

Paraptosis is mediated by several proteins, poly(ADP-ribose) polymerase being one of them. D. discoideum lacks caspases thus providing a better system to dissect out the role of PARP in paraptosis. The cell death phenotype in unicellular eukaryote, D. discoideum is similar to the programmed cell death phenotype of multicellular animals. However, the events downstream to the death signal of PCD in D. discoideum are yet to be understood. Our results emphasize that oxidative stress in D. discoideum lacking caspases leads to PARP activation, mitochondrial membrane potential changes, followed by the release of apoptosis inducing factor from mitochondria. AIF causes large scale DNA fragmentation, a hallmark feature of paraptosis. The role of PARP in paraptosis is reiterated via PARP inhibition by benzamide, PARG inhibition by gallotannin and PARP down-regulation, which delays paraptosis. PARP, PARG and AIF interplay is quintessential in paraptosis of D. discoideum. This is the first report to establish the involvement of PARP in the absence of caspase activity in D. discoideum which could be of evolutionary significance and gives a lead to understand the caspase independent paraptotic mechanism in higher organisms.

Proteases involved during oxidative stress-induced poly(ADP-ribose) polymerase-mediated cell death in Dictyostelium discoideum.

Apoptosis involves a cascade of caspase activation leading to the ordered dismantling of critical cell components. However, little is known about the dismantling process in non-apoptotic cell death where caspases are not involved. Dictyostelium discoideum is a good model system to study caspase-independent cell death where experimental accessibility of non-apoptotic cell death is easier and molecular redundancy is reduced compared with other animal models. Poly(ADP-ribose) polymerase (PARP) is one of the key players in cell death. We have previously reported the role of PARP in development and the oxidative stress-induced cell death of D. discoideum. D. discoideum possesses nine PARP genes and does not have a caspase gene, and thus it provides a better model system to dissect the role of PARP in caspase-independent cell death. The current study shows that non-apoptotic cell death in D. discoideum occurs in a programmed fashion where proteases cause mitochondrial membrane potential changes followed by plasma membrane rupture and early loss of plasma membrane integrity. Furthermore, the results suggest that calpains and cathepsin D, which are instrumental in dismantling the cell, act downstream of PARP. Thus, PARP, apoptosis inducing factor, calpains and cathepsin D are the key players in D. discoideum caspase-independent cell death, acting in a sequential manner.

A novel recessive mutation in the gene ELOVL4 causes a neuro-ichthyotic disorder with variable expressivity.

BACKGROUND: A rare neuro-ichthyotic disorder characterized by ichthyosis, spastic quadriplegia and intellectual disability and caused by recessive mutations in ELOVL4, encoding elongase-4 protein has recently been described. The objective of the study was to search for sequence variants in the gene ELOVL4 in three affected individuals of a consanguineous Pakistani family exhibiting features of neuro-ichthyotic disorder. METHODS: Linkage in the family was searched by genotyping microsatellite markers linked to the gene ELOVL4, mapped at chromosome 6p14.1. Exons and splice junction sites of the gene ELOVL4 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer. RESULTS: DNA sequence analysis revealed a novel homozygous nonsense mutation (c.78C > G; p.Tyr26*). CONCLUSIONS: Our report further confirms the recently described ELOVL4-related neuro-ichthyosis and shows that the neurological phenotype can be absent in some individuals.

Social and Biological Determinants in Lung Cancer Disparity.

Lung cancer remains a leading cause of death in the United States and globally, despite progress in treatment and screening efforts. While mortality rates have decreased in recent years, long-term survival of patients with lung cancer continues to be a challenge. Notably, African American (AA) men experience significant disparities in lung cancer compared to European Americans (EA) in terms of incidence, treatment, and survival. Previous studies have explored factors such as smoking patterns and complex social determinants, including socioeconomic status, personal beliefs, and systemic racism, indicating their role in these disparities. In addition to social factors, emerging evidence points to variations in tumor biology, immunity, and comorbid conditions contributing to racial disparities in this disease. This review emphasizes differences in smoking patterns, screening, and early detection and the intricate interplay of social, biological, and environmental conditions that make African Americans more susceptible to developing lung cancer and experiencing poorer outcomes.

Staurosporine induced poly (ADP-ribose) polymerase independent cell death in Dictyostelium discoideum.

In the present study D. discoideum has been used as a model organism to understand the role of poly (ADP-ribose) polymerase (PARP) in caspase independent paraptotic cell death pathways. D. discoideum lacks caspases and Bcl-2 family proteins; nevertheless it has 9 potential genes for PARP. PARP has been known to get activated in various cell death associated diseases. In this study kinetics of cell death induced by staurosporine (STS), a bacterial alkaloid, was established to unravel the role of PARP. It was found that STS induced cell death in D. discoideum did not involve PARP activation, however it involved cathepsin D. Results indicated that an alternative mechanism may be existing in D. discoideum that lacks Bcl-2 family proteins for STS induced cell death that evades Bax involvement.

The interplay of pineal hormones and socioeconomic status leading to colorectal cancer disparity.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite increased screening options and state-of-art treatments offered in clinics, racial differences remain in CRC. African Americans (AAs) are disproportionately affected by the disease; the incidence and mortality are higher in AAs than Caucasian Americans (CAs). At the time of diagnosis, AAs more often present with advanced stages and aggressive CRCs, primarily accounting for the racial differences in therapeutic outcomes and mortality. The early incidence of CRC in AAs could be attributed to race-specific gene polymorphisms and lifestyle choices associated with socioeconomic status (SES). Altered melatonin-serotonin signaling, besides the established CRC risk factors (age, diet, obesity, alcoholism, and tobacco use), steered by SES, glucocorticoid, and Vitamin D status in AAs could also account for the early incidence in this racial group. This review focuses on how the lifestyle factors, diet, allelic variants, and altered expression of specific genes could lead to atypical serotonin and melatonin signaling by modulating the synthesis, secretion, and signaling of these pineal hormones in AAs and predisposing them to develop more aggressive CRC earlier than CAs. Crosstalk between gut microbiota and pineal hormones and its impact on CRC pathobiology is addressed from a race-specific perspective. Lastly, the status of melatonin-focused CRC treatments, the need to better understand the perturbed melatonin signaling, and the potential of pineal hormone-directed therapeutic interventions to reduce CRC-associated disparity are discussed.

Differential role of poly(ADP-ribose) polymerase in D. discoideum growth and development.

BACKGROUND: Poly(ADP-ribose) polymerase is evolutionarily conserved as a responder to various forms of stress. Though PARP's role in cell death is well addressed, its role in development and multicellularity is still an enigma. We have previously reported the role of PARP in oxidative stress induced delayed development of D. discoideum. RESULTS: In the current study we highlight the involvement of PARP during D. discoideum development. Oxidative stress affects expression of aca and cAR1 thus affecting aggregation. Although parp expression is not affected during oxidative stress but it is involved during normal development as confirmed by our PARP down-regulation studies. Constitutive PARP down-regulation resulted in blocked development while no effect was observed on D. discoideum growth. Interestingly, stage specific PARP down-regulation arrested development at the slug stage. CONCLUSION: These results emphasize that PARP is essential for complex differentiation and its function may be linked to multicellularity. This is the first report where the involvement of PARP during normal multicellular development in D. discoideum, an ancient eukaryote, is established which could be of evolutionary significance. Thus our study adds one more role to the multitasking function of PARP.

CXCR6-CXCL16 Axis Promotes Breast Cancer by Inducing Oncogenic Signaling.

Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis in the pathobiology of BrCa. Our data show a higher expression of CXCR6 in BrCa cell lines and tissues. Stage-III BrCa tissues express significantly higher CXCR6 compared to stage-II tissues. The ligand, CXCL16, could remain tethered to the cell surface, and, after proteolytic shedding of the ectodomain, the N-terminal fragment is released, converting it to its oncogenic, soluble form. Like CXCR6, N-terminal CXCL16 and ADAM-10 were significantly higher in stage-III than stage-II, but no significant difference was observed in the C-terminal fragment of CXCL16. Further, stimulation of the CXCR6/CXCL16 axis activated Src, FAK, ERK1/2, and PI3K signaling pathways, as per antibody microarray analysis, which also underlie CXCL16-induced F-actin polymerization. The CXCR6/CXCL16 axis induces cytoskeleton rearrangement facilitating migration and invasion and supports BrCa cell survival by activating the PI3K/Akt pathway. This study highlights the significance of the CXCR6/CXCL16 axis and ADAM10 as potential therapeutic targets for advanced-stage BrCa.

Racial Differences in Immunological Landscape Modifiers Contributing to Disparity in Prostate Cancer.

Prostate cancer affects African Americans disproportionately by exhibiting greater incidence, rapid disease progression, and higher mortality when compared to their Caucasian counterparts. Additionally, standard treatment interventions do not achieve similar outcome in African Americans compared to Caucasian Americans, indicating differences in host factors contributing to racial disparity. African Americans have allelic variants and hyper-expression of genes that often lead to an immunosuppressive tumor microenvironment, possibly contributing to more aggressive tumors and poorer disease and therapeutic outcomes than Caucasians. In this review, we have discussed race-specific differences in external factors impacting internal milieu, which modify immunological topography as well as contribute to disparity in prostate cancer.