Ire1α RNase-dependent lipid homeostasis promotes survival in myctransformed cancers / Hong Xie.
- Other Title:
- Ire1[alpha] RNase-dependent lipid homeostasis promotes survival in myctransformed cancers
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2018.
ix, 96 leaves : illustrations ; 29 cm
- Local subjects:
- Penn dissertations -- Cell and molecular biology.
Cell and molecular biology -- Penn dissertations.
- Myc family activation is a primary oncogenic event in many human cancers; however, these transcription factors are difficult to inhibit pharmacologically, suggesting that Myc-dependent downstream effectors may be more tractable therapeutic targets. Here, I show that Myc overexpression induces endoplasmic reticulum (ER) stress and engages the IRE1α-XBP1 pathway through multiple molecular mechanisms in a variety of c-Myc- and N-Myc-dependent cancers, e.g. Burkitt’s lymphoma and neuroblastoma. In particular, Myc-overexpressing cells require IRE1α-XBP1 signaling for sustained growth and survival in vitro and in vivo, dependent on elevated stearoyl-CoA-desaturase 1 (SCD1) activity. Pharmacological and genetic XBP1 inhibition induces Myc-dependent apoptosis, which is alleviated by exogenous unsaturated fatty acids. Of note, SCD1 inhibition phenocopies IRE1α RNase activity suppression both in vitro and in vivo. Furthermore, IRE1α inhibition enhances the cytotoxic effects of standard chemotherapy drugs used to treat c-Myc-overexpressing Burkitt’s lymphoma, suggesting that inhibiting the IRE1α-XBP1 pathway is a useful general strategy for treatment of Myc-driven cancers.
- Ph. D. University of Pennsylvania 2018.
Department: Cell and Molecular Biology.
Supervisor: Maria C. Simon.
Includes bibliographical references.
- Simon, Maria C., degree supervisor.
Arany, Zoltan P., degree committee member.
Blair, Ian A., degree committee member.
Koumenis, Constantinos, degree committee member.
Yang, Xiaolu, degree committee member.
University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.
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