Show simple item record

dc.contributor.advisorGaudet, Suzanne
dc.contributor.authorHua, Yijie
dc.date.accessioned2019-12-12T08:15:07Z
dc.date.created2019-05
dc.date.issued2019-05-17
dc.date.submitted2019
dc.identifier.citationHua, Yijie. 2019. Mechanistic Studies of Extrinsic Apoptosis by Therapeutic Molecules in Cancer Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029516*
dc.description.abstractDeath receptor (DR) activation by ligands including TRAIL is the initiating step in extrinsic apoptosis. Despite considerable effort, the clinical benefits from DR agonists have been limited, and no such drug has demonstrated good efficacy in phase II clinical trials. This may be linked to observations that differential cell fate decisions can arise both between cell lines and among individual cells within the same cell line, contributing to resistance to TRAIL and DR therapeutic antibodies in general. Here, I show that DISC activity and caspase-8 dynamics play an important role in extrinsic apoptotic fate decisions for newly engineered ligands. Experiments in cells treated with TRAIL and two novel synthetic TRAIL analogues, T191 and T202, demonstrate that the maximum caspase-8 activation rate threshold is a critical barrier that has to be overcome. In HeLa, DU145, and HT29 cells, this is the major barrier of apoptosis. In HCT116 cells, other factors may also play critical roles in determining cell fate. I also explored potential sensitization strategies in this work in the hope of overcoming pro-survival barriers in TRAIL-resistant cells, and I found that glutamine depletion greatly increased receptor-mediated apoptosis in cells of various cancer types, and this sensitization effect may result from increased caspase-8 activity induced by changes in FLIP and/or TRAF2 levels. I have also determined that the combination of T202 with a proteasome inhibitor (bortezomib) or SMAC mimetic (LCL161) can produce a consistent synergistic effect in multiple breast cancer and colorectal cancer cell lines, pointing to a potentially promising strategy for T202-based treatment.
dc.description.sponsorshipSystems Biology
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectanti-cancer therapeutic molecules
dc.subjectextrinsic apoptosis
dc.subjectTRAIL
dc.subjectcancer resistance
dc.titleMechanistic Studies of Extrinsic Apoptosis by Therapeutic Molecules in Cancer Cells
dc.typeThesis or Dissertation
dash.depositing.authorHua, Yijie
dc.date.available2019-12-12T08:15:07Z
thesis.degree.date2019
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberBrugge, Joan
dc.contributor.committeeMemberAldridge, Bree
dc.contributor.committeeMemberPoltorak, Alexander
dc.type.materialtext
thesis.degree.departmentSystems Biology
thesis.degree.departmentSystems Biology
dash.identifier.vireo
dash.author.emailhuayijie@gmail.com


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record