Date of Degree

5-2019

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Moira Sauane

Committee Members

Frida Kleiman

Stephen Redenti

Pablo Peixoto

Eva Sapi

Subject Categories

Biology | Cancer Biology | Cell Biology

Keywords

cancer, therapeutics, ER stress, translation, protein kinase A, microRNA

Abstract

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, in vitrostudies 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.

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