A Matter of Life and Death: Novel Ligands Mediating Cytotoxic Function and Revealing Metabolically Stimulative Function of the Sigma-2 Receptor in Human Cancer

Nicholson, Hilary E.

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Year:: 2016
Contributor:: Nicholson, Hilary E (creator); Bowen, Wayne (Director); Marshall, John (Reader); Matsumoto, Rae (Reader); Oancea, Elena (Reader); Zhitkovich, Anatoly (Reader); Brown University. BIOMED: Molecular Pharmacology, Physiology, and Biotechnology (sponsor)
Genre:: theses
Subject:: sigma-2 receptor; CM572; CM764; sigma receptor; cellular metabolism; triple negative breast cancer; Glycolysis; Neuroblastoma
Extent:: xxvi, 322 p.
DOI: https://doi.org/10.7301/Z047489K

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Abstract:: The sigma-2 receptor is a pharmacologically-defined protein receptor present in a variety of tissues, and interest in its role in a wide array of diseases has been expanding since its discovery by Wayne Bowen in 1990. Expression is most highly upregulated in rapidly proliferating cancer cells, suggesting a role in cancer cell survival. Although the endogenous ligand has not yet been elucidated, a variety of synthetic agonists have been developed that induce apoptosis upon binding the sigma-2 receptor. This function, coupled with selectively high expression on rapidly proliferating cancer cells, makes the sigma-2 receptor an attractive target for the imaging and treatment of cancer. One such agonist is CM572, an isothiocyanate derivative of the sigma-2 receptor-selective ligand SN79. CM572 irreversibly binds and activates sigma-2 receptors to induce apoptotic cell death at doses that do not cause significant levels of cytotoxicity in non-cancerous cells. Further, CM572 is able to reduce viability of highly aggressive cancers including triple negative breast and pancreatic cancer, suggesting a cell death mechanism that is not susceptible to conventional methods of developing drug resistance that are common in these cancers. Large scale implications for clinical use of CM572 include improved tumor imaging, more selective chemotherapy with reduced off-target adverse effects, and less frequent dosing regimens by virtue of its irreversible binding capability. While CM572 shows great promise as a therapeutic agent, the structurally related SN79 derivative CM764 sheds light on novel aspects of sigma-2 receptor biology. Activation of sigma-2 receptors with CM764 leads to an increase in metabolic reduction of MTT and induction of several hallmarks of glycolysis, including increased HIF-1α protein levels during normoxia and increased expression of VEGF. This stimulation of metabolism was not coupled to proliferation, indicating a unique sigma-2 receptor-mediated potentially pro-survival benefit consistent with the observed upregulation of this receptor in rapidly proliferating tissues. In addition to the discovery of a novel sigma-2 receptor-mediated function, this study may represent a first glimpse into the endogenous mechanism of sigma-2 receptors. Together, these findings demonstrate the ability of sigma-2 receptors to mediate both cytotoxic and pro-survival functions in human cancers.
Notes:: Thesis (Ph.D. -- Brown University (2016)

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Citation

Nicholson, Hilary E., "A Matter of Life and Death: Novel Ligands Mediating Cytotoxic Function and Revealing Metabolically Stimulative Function of the Sigma-2 Receptor in Human Cancer" (2016). Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z047489K

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Molecular Pharmacology, Physiology, and Biotechnology Theses and Dissertations

Theses and Dissertations for the Molecular Pharmacology, Physiology, and Biotechnology department.
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