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Characterization of the unfolded protein response by pharmacological agents in lymphoid malignancies

Sofie Lust (UGent)
(2010)
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Abstract
Normal B cell development is tightly regulated by transcription factors and is characterized by the formation of the B-cell receptor. When the regulation and activation of B cell differentiation is disrupted, lymphomas and leukemias can occur. These lymphoid malignancies often resemble normal stages of the B cell differentiation. During normal B cell development a precursor B cell will ultimately form a terminal differentiated lymphocyte or plasma cell. These terminal differentiated B cells require massive increase in their biosynthetic capacity to synthesize thousands of antibodies per second for secretion. For this purpose, these cells rely on a highly developed endoplasmic reticulum (ER), the compartment where proteins are assembled and modified into functional antibodies. However, upon perturbations in ER function a stress response pathway can be activated, named the "unfolded protein response" (UPR). In the first place, the UPR is a cytoprotective signaling response and several studies have demonstrated already that activation of the UPR might have a crucial role in cancer. Until now, little is known about the role of the UPR in the germinal center (GC)-derived lymphomas since most investigations were performed on healthy B cells and multiple myeloma. Therefore, the initial aim of this doctoral work was to evaluate the expression levels of baseline and inducible UPR-related markers in DLBCL cell lines and in a plasma cell line. Besides its protective role, the UPR may balance in the direction of cell death upon severe and prolonged stress. Manipulation of the UPR may be used as an alternative cell death mechanism since conventional treatments frequently activate the classical cell death pathways, like the intrinsic and extrinsic cell death program. Therefore, this cell death strategy is used on CLL patient samples. To accomplish this goal, the anticancer activities of two plant-derived compounds, xanthohumol (isolated from hop, Humulus lupulus L.) and withaferin A (isolated from Withania somnifera), were investigated. In conclusion, our results provide a scientific basis for further investigations of the involvement of the UPR in DLBCL. Moreover, targeting the ER may be an interesting therapeutic strategy for CLL and other lymphoid malignancies, and for further development of new therapeutic agents.
Keywords
apoptosis, unfolded protein response, CLL, flavonoids, B cell development

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Citation

Please use this url to cite or link to this publication:

Chicago
Lust, Sofie. 2010. “Characterization of the Unfolded Protein Response by Pharmacological Agents in Lymphoid Malignancies”. Ghent, Belgium: Ghent University. Faculty of Medicine and Health Sciences.
APA
Lust, Sofie. (2010). Characterization of the unfolded protein response by pharmacological agents in lymphoid malignancies. Ghent University. Faculty of Medicine and Health Sciences, Ghent, Belgium.
Vancouver
1.
Lust S. Characterization of the unfolded protein response by pharmacological agents in lymphoid malignancies. [Ghent, Belgium]: Ghent University. Faculty of Medicine and Health Sciences; 2010.
MLA
Lust, Sofie. “Characterization of the Unfolded Protein Response by Pharmacological Agents in Lymphoid Malignancies.” 2010 : n. pag. Print.
@phdthesis{1086334,
  abstract     = {Normal B cell development is tightly regulated by transcription factors and is characterized by the formation of the B-cell receptor. When the regulation and activation of B cell differentiation is disrupted, lymphomas and leukemias can occur. These lymphoid malignancies often resemble normal stages of the B cell differentiation. During normal B cell development a precursor B cell will ultimately form a terminal differentiated lymphocyte or plasma cell. These terminal differentiated B cells require massive increase in their biosynthetic capacity to synthesize thousands of antibodies per second for secretion. For this purpose, these cells rely on a highly developed endoplasmic reticulum (ER), the compartment where proteins are assembled and modified into functional antibodies. However, upon perturbations in ER function a stress response pathway can be activated, named the {\textacutedbl}unfolded protein response{\textacutedbl} (UPR). In the first place, the UPR is a cytoprotective signaling response and several studies have demonstrated already that activation of the UPR might have a crucial role in cancer. Until now, little is known about the role of the UPR in the germinal center (GC)-derived lymphomas since most investigations were performed on healthy B cells and multiple myeloma. Therefore, the initial aim of this doctoral work was to evaluate the expression levels of baseline and inducible UPR-related markers in DLBCL cell lines and in a plasma cell line.
Besides its protective role, the UPR may balance in the direction of cell death upon severe and prolonged stress. Manipulation of the UPR may be used as an alternative cell death mechanism since conventional treatments frequently activate the classical cell death pathways, like the intrinsic and extrinsic cell death program. Therefore, this cell death strategy is used on CLL patient samples. To accomplish this goal, the anticancer activities of two plant-derived compounds, xanthohumol (isolated from hop, Humulus lupulus L.) and withaferin A (isolated from Withania somnifera), were investigated.
In conclusion, our results provide a scientific basis for further investigations of the involvement of the UPR in DLBCL. Moreover, targeting the ER may be an interesting therapeutic strategy for CLL and other lymphoid malignancies, and for further development of new therapeutic agents.},
  author       = {Lust, Sofie},
  language     = {eng},
  pages        = {255},
  publisher    = {Ghent University. Faculty of Medicine and Health Sciences},
  school       = {Ghent University},
  title        = {Characterization of the unfolded protein response by pharmacological agents in lymphoid malignancies},
  year         = {2010},
}