The Molecular Mechanisms Underlying the Cancer Killing Effect of Interleukin-24

<p>Interleukin-24 (IL-24) is an immunomodulatory cytokine that also displays specific anti-tumor effects across many cancer cell types. The tumor suppressor activities of IL-24 include inhibition of angiogenesis, metastasis, toxic autophagy, cancer-specific apoptosis, and sensitization to traditional cancer treatments like chemotherapy and radiation. Overexpression of IL-24 can selectively induce apoptosis in various cancer cells while having no adverse effects on normal cells. Due to this favorable killing effect, IL-24 is currently in phase II clinical trials. There is accumulating evidence that IL-24’s anti-cancer activity is primarily through the endoplasmic reticulum (ER) stress pathway but other pathways leading to cell death are also exploited by IL-24 depending on the cell type. In this work, <em>in vitro</em>studies were performed to understand the downstream effects of IL-24-mediated ER stress such as eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation, which leads to ternary complex depletion and translation initiation inhibition. We also uncover a novel mechanism of IL-24-mediated ER stress involving the protein kinase A pathway and extrinsic apoptosis in breast cancer cell lines. Finally, we show for the first time that endogenous IL-24 mRNA expression is affected by the differential expression of microRNA-4719 and microRNA-6756-5p incastration-resistant prostate cancer cell lines compared to normal or indolent prostate cancer cell lines. Each chapter of this work uncovers a new mechanism of action that can be applied to the development of anti-cancer therapeutics involving IL-24. Understanding the intricacies of IL-24-mediated apoptosis in different cancer cell line types will contribute to the development of personalized gene therapies that can target tumors in a more safe and non-toxic approach.</p>

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biology

Grantor

The Graduate School and University Center of The City University of New York

Year dc:date.available

2019

Author dc:creator

• Persaud, Leah Eshanie

Advisor dc:contributor.advisor

• Moira Sauane

Committee members dc:contributor.committeemember

• Frida Kleiman
• Stephen Redenti
• Pablo Peixoto
• Eva Sapi

• Biology
• Cancer Biology
• Cell Biology
• cancer
• therapeutics
• ER stress
• translation
• protein kinase A
• microRNA

Repository record dc:identifier

https://academicworks.cuny.edu/gc_etds/3156

OAI identifier oai:identifier

oai:academicworks.cuny.edu:gc_etds-4209