Gemcitabine Induces Microvesicle Particle Release in a Platelet-Activating Factor-Receptor-Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells

Thyagarajan, Anita; Kadam, Sayali M.; Liu, Langni; Kelly, Lisa E.; Rapp, Christine M.; Chen, Yanfang; Sahu, Ravi P.

doi:10.3390/ijms20010032

Cited by 19 publications

(59 citation statements)

References 41 publications

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“…Among the altered processes in C5a-treated neutrophils, we found MV- relevant processes, such as catabolic and metabolic processes of glycosyl- and glyco-lipids, phospholipids and ceramids as well as activation and regulation of small GTPases ( Supplemental Table 1 ). Further MV-relevant changes in pathways involve cytoskeleton-based processes ( 31 ), cell shape changes, and MAPK activity ( 32 ) ( Supplemental Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

et al. 2020

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Initially underestimated as platelet dust, extracellular vesicles are continuously gaining interest in the field of inflammation. Various studies addressing inflammatory diseases have shown that microvesicles (MVs) originating from different cell types are systemic transport vehicles carrying distinct cargoes to modulate immune responses. In this study, we focused on the clinical setting of multiple trauma, which is characterized by activation and dysfunction of both, the fluid-phase and the cellular component of innate immunity. Given the sensitivity of neutrophils for the complement anaphylatoxin C5a, we hypothesized that increased C5a production induces alterations in MV shedding of neutrophils resulting in neutrophil dysfunction that fuels posttraumatic inflammation. In a mono-centered prospective clinical study with polytraumatized patients, we found significantly increased granulocyte-derived MVs containing the C5a receptor (C5aR1, CD88) on their surface. This finding was accompanied by a concomitant loss of C5aR1 on granulocytes indicative of an impaired cellular chemotactic and pro-inflammatory neutrophil functions. Furthermore, in vitro exposure of human neutrophils (from healthy volunteers) to C5a significantly increased MV shedding and C5aR1 loss on neutrophils, which could be blocked using the C5aR1 antagonist PMX53. Mechanistic analyses revealed that the interaction between C5aR1 signaling and the small GTPase Arf6 acts as a molecular switch for MV shedding. When neutrophil derived, C5a-induced MV were exposed to a complex ex vivo whole blood model significant pro-inflammatory properties (NADPH activity, ROS and MPO generation) of the MVs became evident. C5a-induced MVs activated resting neutrophils and significantly induced IL-6 secretion. These data suggest a novel role of the C5a-C5aR1 axis: C5a-induced MV shedding from neutrophils results in decreased C5aR1 surface expression on the one hand, on the other hand it leads to profound inflammatory signals which likely are both key drivers of the neutrophil dysfunction which is regularly observed in patients suffering from multiple traumatic injuries.

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Section: Resultsmentioning

confidence: 99%

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

et al. 2020

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“…However, the role of the PAFR signaling in modulating targeted therapy effects in lung cancer models has not been studied. Given that these PAF agonists are metabolically labile and upon generation get readily metabolized by PAF-AH, our recent studies have defined the critical roles of a subpopulation of extracellular vesicles known as microvesicles or microvesicle particles as a novel mechanism by which these potent lipids are not only protected but circulated to exert local as well as delayed systemic effects [ 34 , 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells

Chauhan

Thyagarajan

Chen

et al. 2020

IJMS

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Microvesicle particles (MVP) secreted by a variety of cell types in response to reactive oxygen species (ROS)-generating pro-oxidative stressors have been implicated in modifying the cellular responses including the sensitivity to therapeutic agents. Our previous studies have shown that expression of a G-protein coupled, platelet-activating factor-receptor (PAFR) pathway plays critical roles in pro-oxidative stressors-mediated cancer growth and MVP release. As most therapeutic agents act as pro-oxidative stressors, the current studies were designed to determine the role of the PAFR signaling in targeted therapies (i.e., gefitinib and erlotinib)-mediated MVP release and underlying mechanisms using PAFR-expressing human A549 and H1299 non-small cell lung cancer (NSCLC) cell lines. Our studies demonstrate that both gefitinib and erlotinib generate ROS in a dose-dependent manner in a process blocked by antioxidant and PAFR antagonist, verifying their pro-oxidative stressor’s ability, and the role of the PAFR in this effect. We observed that these targeted therapies induce MVP release in a dose- and time-dependent manner, similar to a PAFR-agonist, carbamoyl-PAF (CPAF), and PAFR-independent agonist, phorbol myristate acetate (PMA), used as positive controls. To confirm the PAFR dependency, we demonstrate that siRNA-mediated PAFR knockdown or PAFR antagonist significantly blocked only targeted therapies- and CPAF-mediated but not PMA-induced MVP release. The use of pharmacologic inhibitor strategy suggested the involvement of the lipid ceramide-generating enzyme, acid sphingomyelinase (aSMase) in MVP biogenesis, and observed that regardless of the stimuli used, aSMase inhibition significantly blocked MVP release. As mitogen-activated protein kinase (MAPK; ERK1/2 and p38) pathways crosstalk with PAFR, their inhibition also significantly attenuated targeted therapies-mediated MVP release. These findings indicate that PAFR signaling could be targeted to modify cellular responses of targeted therapies in lung cancer cells.

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“…PRAS40 downregulated Akt, downstream of TGF-β, and mediated antagonistic effects against exosome secretion and chemoresistance in breast and lung cancer cells [ 123 ]. WEB2086, a platelet-activating factor receptor (PAFR) antagonist, was shown to reduce gemcitabine-induced exosome release in PAFR-positive pancreatic cancer cells [ 124 ]. Other exosome extrusion inhibitors, such as chloramidine, bisindolylmaleimide-I, imipramine, d-pantethine, and calpeptin, and calcium chelators, such as ethylene glycol bis (2-aminoethyl ether) tetra-acetic acid, increased responsiveness toward 5-FU in prostate and BC cells [ 125 ].…”

Section: Strategies Against Tumor-derived Exosomesmentioning

confidence: 99%

Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy

Sinha

Roy

Saha

et al. 2021

Cancers

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Exosomes, the endosome-derived bilayered extracellular nanovesicles with their contribution in many aspects of cancer biology, have become one of the prime foci of research. Exosomes derived from various cells carry cargoes similar to their originator cells and their mode of generation is different compared to other extracellular vesicles. This review has tried to cover all aspects of exosome biogenesis, including cargo, Rab-dependent and Rab-independent secretion of endosomes and exosomal internalization. The bioactive molecules of the tumor-derived exosomes, by virtue of their ubiquitous presence and small size, can migrate to distal parts and propagate oncogenic signaling and epigenetic regulation, modulate tumor microenvironment and facilitate immune escape, tumor progression and drug resistance responsible for cancer progression. Strategies improvised against tumor-derived exosomes include suppression of exosome uptake, modulation of exosomal cargo and removal of exosomes. Apart from the protumorigenic role, exosomal cargoes have been selectively manipulated for diagnosis, immune therapy, vaccine development, RNA therapy, stem cell therapy, drug delivery and reversal of chemoresistance against cancer. However, several challenges, including in-depth knowledge of exosome biogenesis and protein sorting, perfect and pure isolation of exosomes, large-scale production, better loading efficiency, and targeted delivery of exosomes, have to be confronted before the successful implementation of exosomes becomes possible for the diagnosis and therapy of cancer.

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Gemcitabine Induces Microvesicle Particle Release in a Platelet-Activating Factor-Receptor-Dependent Manner via Modulation of the MAPK Pathway in Pancreatic Cancer Cells

Cited by 19 publications

References 41 publications

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

Complement C5a Induces Pro-inflammatory Microvesicle Shedding in Severely Injured Patients

Platelet-Activating Factor-Receptor Signaling Mediates Targeted Therapies-Induced Microvesicle Particles Release in Lung Cancer Cells

Trends in Research on Exosomes in Cancer Progression and Anticancer Therapy

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