Abstract
Macroautophagy can promote cellular survival or death depending on the cellular context and its extent. We hypothesized that autophagy induction would synergize with a therapeutic agent targeting the autophagic cargo. To test this hypothesis, we treated breast cancer MDA-MB-231 cells with tamoxifen (TMX), which induces autophagy through an estrogen receptor-independent pathway. Induction of autophagy reduced cellular levels of RRM2, a subunit of ribonucleotide reductase (RR), the rate limiting enzyme in the production of deoxyribonucleotide triphosphates (dNTPs). This autophagy inducer was combined with COH29, an inhibitor developed in our laboratory that targets RR through a novel mechanism. The combination therapy showed synergistic effects on cytotoxicity in vitro and in an in vivo xenograft model. This cytotoxicity was blocked by knockdown of the autophagy protein ATG5 or addition of chloroquine, an autophagy inhibitor. The combined therapy also induced dNTP depletion and massive genomic instability, leading us to hypothesize that combining autophagy induction with RR inhibition can lead to mitotic catastrophe in rapidly dividing cells. We propose that this TMX + COH29 combined therapy may have clinical benefit. Furthermore, autophagy induction may be a general mechanism for augmenting the effects of chemotherapeutic agents.
Highlights
Cell death is an important process in cancer therapy that occurs through three major pathways: apoptosis, autophagy, and necrosis - each of which can be characterized by various morphological criteria [1]
Based on our previous work [30], we hypothesized that inducing autophagy would decrease RRM2 levels and sensitize cancer cells to COH29, a novel ribonucleotide reductase (RR) inhibitor [12, 31]
Numerous small molecule inhibitors, such as hydroxyurea (HU), gemcitabine and triapine [47], interact with the RRM2 subunit and inhibit RR activity
Summary
Cell death is an important process in cancer therapy that occurs through three major pathways: apoptosis, autophagy, and necrosis - each of which can be characterized by various morphological criteria [1]. Autophagy is a self-degradative pathway for disposal of obsolete parts of the cell, is accompanied by vacuolization in the cytoplasm and can lead to increased cell survival or cell death depending on the type and extent of self-degradation [2]. Organelles and parts of the cytoplasm are isolated in characteristic double-membrane organelles known as autophagosomes. Necrosis is defined as a type of cell death that lacks features of the two previous pathways and is accompanied by swelling of the cell, loss of membrane integrity, and inflammatory response, as the cellular contents are released into the extracellular environment [1]. Cell death pathways play important roles in tumorigenesis, cancer progression, and resistance to therapy and are important therapeutic targets in cancer [7]
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