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Chronic nickel exposure alters extracellular vesicles to mediate cancer progression via sustained NUPR1 expression

Liu, Shan; Costa, Max; Ortiz, Angelica
Cancer cells release extracellular vesicles (EVs) that participate in altering the proximal tumor environment and distal tissues to promote cancer progression. Chronic exposure to nickel (Ni), a human group I carcinogen, results in epigenetic changes that promotes epithelial to mesenchymal transition (EMT). Cells that undergo EMT demonstrate various molecular changes, including elevated levels of the mesenchymal cadherin N-cadherin (N-CAD) and the transcription factor Zinc finger E-box binding homeobox 1 (ZEB1). Moreover, the molecular changes following EMT induce changes in cellular behavior, including anchorage-independent growth, which contributes to cancer cells detaching from tumor bulk during the metastatic process. Here, we present data demonstrating that EVs from Ni-exposed cells induce EMT in recipient BEAS-2B cells in the absence of Ni. Moreover, we show evidence that the EVs from Ni-altered cells package the transcription factor nuclear protein 1 (NUPR1), a transcription factor associated with Ni exposure and cancer progression. Moreover, our data demonstrates that the NUPR1 in the EVs becomes part of the recipient cell proteomic milieu and carry the NUPR1 to the nuclear space of the recipient cell. Interestingly, knockdown of NUPR1 in Ni-transformed cells suppressed NUPR1 packaging in the EVs, and nanoparticle tracking analysis (NTA) demonstrated decreased EV release. Reduction of NUPR1 in EVs resulted in diminished EMT capacity that resulted in decreased anchorage independent growth. This study is the first to demonstrate the role of NUPR1 in extracellular vesicle-mediate cancer progression.
SCOPUS:85182009665
ISSN: 0162-0134
CID: 5629002

Chronic nickel exposure alters extracellular vesicles to mediate cancer progression via sustained NUPR1 expression

Liu, Shan; Costa, Max; Ortiz, Angelica
Cancer cells release extracellular vesicles (EVs) that participate in altering the proximal tumor environment and distal tissues to promote cancer progression. Chronic exposure to nickel (Ni), a human group I carcinogen, results in epigenetic changes that promotes epithelial to mesenchymal transition (EMT). Cells that undergo EMT demonstrate various molecular changes, including elevated levels of the mesenchymal cadherin N-cadherin (N-CAD) and the transcription factor Zinc finger E-box binding homeobox 1 (ZEB1). Moreover, the molecular changes following EMT induce changes in cellular behavior, including anchorage-independent growth, which contributes to cancer cells detaching from tumor bulk during the metastatic process. Here, we present data demonstrating that EVs from Ni-exposed cells induce EMT in recipient BEAS-2B cells in the absence of Ni. Moreover, we show evidence that the EVs from Ni-altered cells package the transcription factor nuclear protein 1 (NUPR1), a transcription factor associated with Ni exposure and cancer progression. Moreover, our data demonstrates that the NUPR1 in the EVs becomes part of the recipient cell proteomic milieu and carry the NUPR1 to the nuclear space of the recipient cell. Interestingly, knockdown of NUPR1 in Ni-transformed cells suppressed NUPR1 packaging in the EVs, and nanoparticle tracking analysis (NTA) demonstrated decreased EV release. Reduction of NUPR1 in EVs resulted in diminished EMT capacity that resulted in decreased anchorage independent growth. This study is the first to demonstrate the role of NUPR1 in extracellular vesicle-mediate cancer progression.
PMID: 38199052
ISSN: 1873-3344
CID: 5627632

NUPR1 packaged in extracellular vesicles promotes murine triple-negative breast cancer in a type 1 interferon-independent manner

Ortiz, Angelica; Stavrou, Aikaterini; Liu, Shan; Chen, Danqi; Shen, Steven S.; Jin, Chunyuan
Aim: This study aims to elucidate the involvement of triple-negative breast cancer (TNBC)-derived extracellular vesicles in metastasis. The loss of components in the type 1 interferon (IFN1) signaling pathway has been linked to the promotion of metastasis. However, IFN1 signaling induces immunological dormancy and promotes tumorigenesis. Our hypothesis was that TNBC cells release tumor-derived extracellular vesicles (TEVs) that promote metastasis in an IFN1-independent manner. Methods: Two murine TNBC models and transgenic mice were used to examine the role of IFN1 in TNBC progression to metastasis. Reserpine was employed to determine the effect of TEV education on TNBC progression and overall survival. EVs from cancer cells treated with vehicle and reserpine and from the serum of tumor-bearing mice receiving reserpine were examined to determine changes in EV release and EV content. Results: TNBC cells progress to metastasis in mice lacking the IFN1-induced gene cholesterol-25 hydroxylase (CH25H) or expressing the IFNAR1S526 knock-in that cannot be downregulated. Reserpine suppresses EV release from TNBC cells in vitro and in vivo. Western blot analysis demonstrated reserpine decreased NUPR1 protein levels in EVs. RNAseq analysis demonstrated that endothelial cells lacking CH25H treated with TEVs exhibited increased NUPR1 expression that was decreased by adding reserpine with the TEVs. NUPR1 overexpression upregulated genes that mediate TEV biogenesis and incorporation. Knockdown of NUPR1 with shRNA decreased the release of TEVs. Conclusion: In conclusion, our study suggests that TNBC is driven by aberrant packaging of NUPR1 into TEVs which were transferred into recipient cells to activate pro-metastatic transcription driven by NUPR1.
SCOPUS:85183374487
ISSN: 2767-6641
CID: 5631762

A combination of three antioxidants decreases the impact of rural particulate pollution in Normal human keratinocytes

Ortiz, Angelica; Sun, Hong; Kluz, Thomas; Matsui, Mary S; Carle, Tiffany; Gan, David; Gordon, Terry; Gildea, Lucy; Costa, Max
OBJECTIVE:), is associated with oxidative stress, DNA damage and inflammation, leading to premature signs of skin aging. Because much of the damage results from oxidative stress, we examined the effects of a topical composition containing three antioxidants in an in vitro model system to assess the potential for amelioration of premature aging. The use of multiple antioxidants was of interest based on the typical composition of therapeutic skincare products. It is important to determine the efficacy of multiple antioxidants together and develop a short-term assay for larger scale efficacy testing. METHODS:in the presence and absence of an antioxidant mixture of resveratrol, niacinamide and GHK peptide. Endpoints related to inflammation, premature aging and carcinogenicity were monitored after 5 h of exposure and included IL-6, CXCL10, MMP-1 and NRF2. Differentially expressed genes were monitored by RNA-seq. RESULTS:and suppressed by antioxidants. CONCLUSIONS:Specific signalling pathways known to be correlated with skin inflammation and aging were examined based on their suitability for use in efficacy testing for the prevention of skin damage due to ambient hydrocarbon pollution. Endpoints examined after only 5 h of exposure provide a useful method amenable to high through-put screening. The results obtained reinforce the concept that a multiple antioxidant preparation, topically applied, may reduce pro-inflammatory signalling and cellular damage and thereby reduce premature skin aging due to exposure to rural-derived airborne pollution.
PMID: 37602524
ISSN: 1468-2494
CID: 5598212

Cadmium Activates EGFR/STAT5 Signaling to Overcome Calcium Chelation and Promote Epithelial to Mesenchymal Transition

Stavrou, Aikaterini; Ortiz, Angelica; Costa, Max
Cadmium (Cd) is a heavy metal found in cigarette smoke, as well as in air and drinking water due to agricultural and industrial activities, and it poses a health risk to the general population. Prolonged low-dose Cd exposure via inhalation or ingestion causes lung and kidney cancers in humans and in animal models. While high doses of Cd exposure are correlated with the occupational setting and are cytotoxic, low doses of Cd are mainly correlated with exposure in the general population and induce carcinogenesis. The mechanism by which Cd-exposed cells overcome calcium chelation and induce malignant transformation remains unclear. This study examines how cells exposed to low doses of Cd survive loss of E-cadherin cell-cell adhesion via activation of the epidermal growth factor receptor (EGFR) and signal transducer and activator of transcription 5 (STAT5), which work to upregulate genes associated with survival and proliferation. To demonstrate the role of Cd in EGFR/STAT5 activation, we exposed two epithelial cell lines, BEAS-2B and HEK293, to two different doses (0.4 µM and 1.6 µM) of Cadmium chloride hemipentahydrate (CdCl2·2.5H2O) that are environmentally relevant to levels of Cd found in food and cigarettes for 24 h (hours) and 9 weeks (wks). When comparing cells treated with Cd with control cells, the Cd treated cells exhibited faster proliferation; therefore, we studied activation of EGFR via the STAT5 pathway using immunofluorescence (IF) for protein expression and localization and, in addition, RT-qPCR to examine changes in EGFR/STAT5 inducible genes. Our results showed an increase in EGFR and phosphorylated EGFR (p-EGFR) protein, with 1.6 µM of Cadmium having the highest expression at both 24-hour (hr) and 9-week (wk) exposures. Moreover, the IF analysis also demonstrated an increase of STAT5 and phosphorylated STAT5 (pSTAT5) in both short-term and long-term exposure, with 0.4 µM having the highest expression at 24 h. Finally, via Western blot analysis, we showed that there was a dose-dependent decrease in E-cadherin protein expression and increased N-cadherin in cells treated with low doses of Cd. These data demonstrate that epithelial cells can overcome Cd-mediated toxicity via activation of EGFR pathway to induce cell proliferation and survival and promote epithelial to mesenchymal transition.
PMCID:9855692
PMID: 36671501
ISSN: 2218-273x
CID: 5426442

Extracellular Vesicles as Mediators of Nickel-Induced Cancer Progression

Liu, Shan; Ortiz, Angelica; Stavrou, Aikaterini; Talusan, Angela R; Costa, Max
Emerging evidence suggests that extracellular vesicles (EVs), which represent a crucial mode of intercellular communication, play important roles in cancer progression by transferring oncogenic materials. Nickel (Ni) has been identified as a human group I carcinogen; however, the underlying mechanisms governing Ni-induced carcinogenesis are still being elucidated. Here, we present data demonstrating that Ni exposure generates EVs that contribute to Ni-mediated carcinogenesis and cancer progression. Human bronchial epithelial (BEAS-2B) cells and human embryonic kidney-293 (HEK293) cells were chronically exposed to Ni to generate Ni-treated cells (Ni-6W), Ni-transformed BEAS-2B cells (Ni-3) and Ni-transformed HEK293 cells (HNi-4). The signatures of EVs isolated from Ni-6W, Ni-3, HNi-4, BEAS-2B, and HEK293 were analyzed. Compared to their respective untreated cells, Ni-6W, Ni-3, and HNi-4 released more EVs. This change in EV release coincided with increased transcription of the EV biogenesis markers CD82, CD63, and flotillin-1 (FLOT). Additionally, EVs from Ni-transformed cells had enriched protein and RNA, a phenotype also observed in other studies characterizing EVs from cancer cells. Interestingly, both epithelial cells and human umbilical vein endothelial (HUVEC) cells showed a preference for taking up Ni-altered EVs compared to EVs released from the untreated cells. Moreover, these Ni-altered EVs induced inflammatory responses in both epithelial and endothelial cells and increased the expression of coagulation markers in endothelial cells. Prolonged treatment of Ni-alerted EVs for two weeks induced the epithelial-to-mesenchymal transition (EMT) in BEAS-2B cells. This study is the first to characterize the effect of Ni on EVs and suggests the potential role of EVs in Ni-induced cancer progression.
PMCID:9785150
PMID: 36555753
ISSN: 1422-0067
CID: 5394752

Extracellular Vesicles: A Novel Tool in Nanomedicine and Cancer Treatment

Stavrou, Aikaterini; Ortiz, Angelica
Extracellular vesicles are membrane-bound vesicles released by cells to mediate intercellular communication and homeostasis. Various external stimuli as well as inherent abnormalities result in alterations in the extracellular vesicle milieu. Changes to cells result in alterations in the content of the extracellular vesicle biogenesis, which may affect proximal and distal cells encountering these altered extracellular vesicles. Therefore, the examination of changes in the extracellular vesicle signature can be used to follow disease progression, reveal possible targets to improve therapy, as well as to serve as mediators of therapy. Furthermore, recent studies have developed methods to alter the cargo of extracellular vesicles to restore normal function or deliver therapeutic agents. This review will examine how extracellular vesicles from cancer cells differ from normal cells, how these altered extracellular vesicles can contribute to cancer progression, and how extracellular vesicles can be used as a therapeutic agent to target cancer cells and cancer-associated stroma. Here we present extracellular vesicles as a novel tool in nanomedicine.
PMCID:9497055
PMID: 36139610
ISSN: 2072-6694
CID: 5335672

Targeting PARP11 to avert immunosuppression and improve CAR T therapy in solid tumors

Zhang, Hongru; Yu, Pengfei; Tomar, Vivek S; Chen, Xiangjie; Atherton, Matthew J; Lu, Zhen; Zhang, Hong-Guang; Li, Shifeng; Ortiz, Angelica; Gui, Jun; Leu, N Adrian; Yan, Fangxue; Blanco, Andres; Meyer-Ficca, Mirella L; Meyer, Ralph G; Beiting, Daniel P; Li, Jinyang; Nunez-Cruz, Selene; O'Connor, Roddy S; Johnson, Lexus R; Minn, Andy J; George, Subin S; Koumenis, Constantinos; Diehl, J Alan; Milone, Michael C; Zheng, Hui; Fuchs, Serge Y
Evasion of antitumor immunity and resistance to therapies in solid tumors are aided by an immunosuppressive tumor microenvironment (TME). We found that TME factors, such as regulatory T cells and adenosine, downregulated type I interferon receptor IFNAR1 on CD8+ cytotoxic T lymphocytes (CTLs). These events relied upon poly-ADP ribose polymerase-11 (PARP11), which was induced in intratumoral CTLs and acted as a key regulator of the immunosuppressive TME. Ablation of PARP11 prevented loss of IFNAR1, increased CTL tumoricidal activity and inhibited tumor growth in an IFNAR1-dependent manner. Accordingly, genetic or pharmacologic inactivation of PARP11 augmented the therapeutic benefits of chimeric antigen receptor T cells. Chimeric antigen receptor CTLs engineered to inactivate PARP11 demonstrated a superior efficacy against solid tumors. These findings highlight the role of PARP11 in the immunosuppressive TME and provide a proof of principle for targeting this pathway to optimize immune therapies.
PMID: 35637402
ISSN: 2662-1347
CID: 5303422

Effects of metallic elements on reproduction and development

Chapter by: De Palma, Giuseppe; Ortiz, Angelica; Apostoli, Pietro
in: Handbook on the Toxicology of Metals by
[S.l.] : Elsevier, 2021
pp. 565-592
ISBN: 9780128232927
CID: 5317142

Effects of metals on extracellular vesicle signaling

Chapter by: Liu, Shan; Costa, Max; Ortiz, Angelica
in: Handbook on the Toxicology of Metals by
[S.l.] : Elsevier, 2021
pp. 279-298
ISBN: 9780128232927
CID: 5317152