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The Role of Orai-Mediated Ca2+ Entry in Migration in a Gastroenteropancreatic Neuroendocrine Tumor Model

Goswamee, Priyodarshan
http://rave.ohiolink.edu/etdc/view?acc_num=mco1438280470

Abstract Details

2015, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Neurosciences and Neurological Disorders).
Gastroenteropancreatic neuroendocrine tumors (GEPNETs) of the midgut are a heterogeneous group of cancers that typically remain asymptomatic until they metastasize to the liver. However, the mechanism by which these usually indolent neoplasms establish distal metastasis remains unclear. The results presented in this dissertation support the hypothesis that arachidonic acid-induced Ca2+ entry through an Orai3-containing channel enhances GEPNET cell migration and contribute to tumor cell extravasation through the hepatic microvasculature. Using a novel liver slice preparation in combination with ultrastructure analysis, we demonstrated that a subpopulation of BON cells, a well-characterized GEPNET cell line, opportunistically migrated through the discontinuous sinusoidal endothelium and redistributed into the liver parenchyma within 24 hours following their introduction to the sinusoids. In a parallel set of studies, we identified a novel Ca2+ entry pathway through an Orai-containing channel that enhanced the migratory capacity of a subpopulation of these tumor cells. Orai-containing channels are known to underlie Ca2+ entry in response to both store-depletion and activation by arachidonic acid (AA) or its metabolites. In recent years, the store-operated Ca2+ entry (SOCE) has been implicated in the migration of some cancer cell lines. However, the role of AA-induced Ca2+ entry in cancer cell migration has not been adequately assessed. We investigated the involvement of AA-induced Ca2+ entry in migration in BON cells using live cell fluorescence imaging and standard migration assays in combination with pharmacological and gene knockdown methods. We showed that both SOCE and AA-induced Ca2+ entry modes could be selectively activated and inhibited. Administration of AA resulted in Ca2+ entry that was pharmacologically distinct from SOCE. Moreover, whereas homomeric Orai1-containing channels appeared to largely underlie SOCE, the AA-activated Ca2+ channel required expression of Orai3 as well as, Orai1. Furthermore, we showed that treatment with AA enhanced migration of BON cells and that this enhancement could be abrogated by selective inhibition of the AA-induced Ca2+ entry, whereas activation of SOCE did not enhance migration. In addition, the AA-induced Ca2+ entry and SOCE appeared to be reciprocally repressive suggesting the possibility that the balance between these two pathways sets the migratory potential of these tumor cells. Taken together, we identified Ca2+ entry through the Orai3-containing channel as a novel signal for BON cell migration that may be exploited to develop therapies to limit recurring GEPNET metastasis.
David Giovannucci (Committee Chair)
Kathryn Eisenmann (Committee Member)
William Gunning III (Committee Member)
Marthe Howard (Committee Member)
William Maltese (Committee Member)
Joshua Park (Committee Member)
151 p.
Biomedical Research
Calcium signaling; Orai1; Orai3; Arachidonate induced Calcium entry; Store operated Calcium entry; Tumor extravasation; Liver metastasis; Carcinoids; Gastroenteropancreatic neuroendocrine tumors

Recommended Citations

Citations

  • Goswamee, P. (2015). The Role of Orai-Mediated Ca2+ Entry in Migration in a Gastroenteropancreatic Neuroendocrine Tumor Model [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438280470

    APA Style (7th edition)

  • Goswamee, Priyodarshan. The Role of Orai-Mediated Ca2+ Entry in Migration in a Gastroenteropancreatic Neuroendocrine Tumor Model. 2015. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1438280470.

    MLA Style (8th edition)

  • Goswamee, Priyodarshan. "The Role of Orai-Mediated Ca2+ Entry in Migration in a Gastroenteropancreatic Neuroendocrine Tumor Model." Doctoral dissertation, University of Toledo, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=mco1438280470

    Chicago Manual of Style (17th edition)

mco1438280470
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© 2015, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.