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Investigating Novel Targets to Inhibit Cancer Cell Survival

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dc.contributor.authorPridham, Kevin J.en
dc.contributor.committeechairSheng, Zhien
dc.contributor.committeememberGourdie, Robert G.en
dc.contributor.committeememberSchmelz, Eva M.en
dc.contributor.committeememberTheus, Michelle H.en
dc.contributor.committeememberVaughn, Jennifer E.en
dc.contributor.departmentGraduate Schoolen
dc.date.accessioned2018-04-19T14:58:32Zen
dc.date.available2018-04-19T14:58:32Zen
dc.date.issued2018-04-18en
dc.description.abstractCancer remains the second leading cause of death in the United States and the world, despite years of research and the development of different treatments. One reason for this is cancer cells are able to survive through adaptation to their environment and aberrantly activated growth signaling. As such, developing new therapies that overcome these hurdles are necessary to combat cancer. Previous work in our laboratory using RNA interference screening identified genes that regulate the survival of glioblastoma (GBM) or autophagy in chronic myelogenous leukemia (CML) cancer cells. One screen identified Phosphatidylinositol-4,5-bisophosphate 3-kinase catalytic subunit beta (PIK3CB) in the family of Phosphatidylinositol 3-kinases (PI3K) as a survival kinase gene in GBM. Work contained in this dissertation set out to study PIK3CB mediated GBM cell survival. We report that only PIK3CB, in its family of other PI3K genes, is a biomarker for GBM recurrence and is selectively important for GBM cell survival. Another screen identified the long non-coding RNA, Linc00467, as a gene that regulates autophagy in CML. Autophagy is a dynamic survival process used by all cells, benign and cancerous, where cellular components are broken down and re-assimilated to sustain survival. Work contained in this dissertation set out to characterize the role that Linc00467 serves in regulating autophagy in a myriad of cancers. Collectively our data have showed Linc00467 to actively repress levels of autophagy in cancer cells. Further, our data revealed an important role for Linc00467 in regulating the stability of the autophagy regulating protein serine-threonine kinase 11 (STK11). Because of the unique role that Linc00467 serves in regulating autophagy we renamed it as, autophagy regulating long intergenic noncoding RNA or ARLINC. Taken together the work in this dissertation unveils the inner-workings of two important cancer cell survival pathways and shows their potential for development into therapeutic targets to treat cancer.en
dc.description.abstractgeneralCancer remains the second leading cause of death in the United States and the world, despite years of research and the development of different treatments. One reason for this is cancer cells are able to survive through adaptation to their environment and aberrantly activated growth signaling. As such, developing new therapies that overcome these hurdles are necessary to combat cancer. Previous work in our laboratory using high throughput genetic screens identified genes that regulate the survival of cancer cells from a deadly type of brain cancer called glioblastoma (GBM). Another screen revealed genes that regulate a process called autophagy in cancer cells from a type of leukemia called chronic myelogenous leukemia (CML). Autophagy is a process that cancer cells can use to survive through chemotherapy. One screen identified the gene Phosphatidylinositol-4,5-bisophosphate 3-kinase catalytic subunit β (PIK3CB) in the family of Phosphatidylinositol 3-kinases (PI3K) as a survival gene in GBM. Work contained in this dissertation set out to study PIK3CB mediated GBM cell survival. We report that only PIK3CB, in its family of other PI3K genes, is a biomarker for GBM recurrence and is selectively important for GBM cell survival. Another screen identified the long non-coding RNA, Linc00467, as a gene that regulates autophagy in CML. Autophagy is a dynamic survival process used by all cells, normal and cancerous, where cellular components are broken down and reassimilated to sustain survival. Work contained in this dissertation set out to characterize the role that Linc00467 serves in regulating autophagy in different types of cancer. Collectively our data have showed Linc00467 to actively repress levels of autophagy in cancer cells. Further, our data revealed an important role for Linc00467 in regulating the stability of the autophagy regulating protein serine-threonine kinase 11 (STK11). Because of the unique role that Linc00467 serves in regulating autophagy we renamed it as, autophagy regulating long intergenic noncoding RNA or ARLINC. Taken together the work in this dissertation unveils the inner-workings of two important cancer cell survival pathways and shows their potential for development into therapeutic targets to treat cancer.en
dc.description.degreePh. D.en
dc.format.mediumETDen
dc.identifier.othervt_gsexam:14459en
dc.identifier.urihttp://hdl.handle.net/10919/82855en
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectcanceren
dc.subjectglioblastomaen
dc.subjecttumor recurrenceen
dc.subjectPI3Ken
dc.subjectchronic myelogenous leukemiaen
dc.subjectautophagyen
dc.subjectnon-coding RNAsen
dc.subjectdrug resistanceen
dc.titleInvestigating Novel Targets to Inhibit Cancer Cell Survivalen
dc.typeDissertationen
thesis.degree.disciplineTranslational Biology, Medicine and Healthen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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