Date of Degree

2-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Moira Sauane

Committee Members

Frida Kleiman

Stephen Redenti

Diago Loayza

Yan Zhu

Subject Categories

Cancer Biology

Keywords

cancer, interleukin 24, sigma 1 receptor, mitochondrium

Abstract

Cancers develop as some cells acquire the ability, either by exogenous stimulation or by spontaneous mutation, to keep growing despite normal restraints. Up-regulating translation of oncogenes involved in cell proliferation and tumor development and down-regulating translation of tumor-suppressors that normally suppress tumor development are two most common mechanisms by which cancers develop. Therefore, it is crucial to study how these proteins get either up-regulated or down-regulated at translational level.

The eukaryotic translation initiation factor, which is composed of subunits such as eIF4A, eIF4G and eIF4E, is one of the key factors that contribute to efficient translation initiation. Interleukin 24 (IL-24), otherwise known as melanoma differentiation associated gene-7 (mda-7), is endogenously expressed by epidermal and immune cells and involved in wound repairing and fighting inflammation. Overexpression of IL-24 in cell lines is able to selectively induce apoptosis in various cancer cells while leaving normal cells intact (Sainz-Perez et al., 2008; Sauane et al., 2003; Persaud et al., 2016; Lebedeva et al., 2002; Jiang et al., 1996; Gopalan et al., 2007; Chada et al., 2005; Fonseca-Camarillo et al., 2014). Given this specific killing effect, IL-24 is being studied extensively and currently in phase II clinical trials as a promising cancer therapeutic. Sigma 1 receptor and mitochondrial dysfunction have been both found to be involved in cancer development and treatment as well. The primary focus of this my thesis is that IL-24 exerts its anticancer effects by restraining translation initiation of some key mRNAs for oncogenes by inhibiting subunits of eIF4F complex and inducing mitochondrial membrane disruption, and Sigma 1 receptor can rescue this killing effect by IL-24. Inhibition of inhibitory immune checkpoint such as PD-L1 is suggested to be part of the network by which IL-24 inhibits cancer cells. This work uncovers some new mechanisms of action that can be exploited to help develop anti-cancer therapeutics mainly composed of IL-24. Uncovering the details of IL-24-mediated apoptosis in various cancer cell lines will help develop personalized immune-therapies that can treat tumors in a more efficient and safer fashion.

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