The Centre of Molecular and Environmental Biology outlines how yeast can clarify the regulation of cell death pathways and provide new therapeutic strategies for human diseases
Regulated cell death (RCD) is under tight genetic control, allowing a cell to trigger its own suicide. Apoptosis, the best-characterised RCD process, is crucial to eliminate damaged cells, avoid virus spreading from infected cells, and maintain tissue homeostasis. When the latter is compromised, different human pathologies often arise, such as cancer and neurodegenerative diseases. Until recently, due to a perceived beneficial role only to multicellular organisms and to the difficulty in finding orthologues of the core mammalian cell death machinery, apoptosis was thought to be confined to higher eukaryotes. However, a large body of evidence emerged in the late nineties supporting a physiological role for apoptosis, as well as other forms of RCD, in lower eukaryotes such as the baker´s yeast Saccharomyces cerevisiae.
The added advantage of easy handling and genetic tractability, including the ectopic expression of human genes while preserving their functional role and without interference from the mammalian complex regulatory network, makes yeast a powerful and suitable model organism to approach key questions on cell death and its deregulation in humans. This fostered the field of yeast cell death, which we embraced from the early beginning, since we believed it offered great potential to highlight molecular mechanisms underlying death processes and their regulation.
Cell death research
As a result of several years of research in this field, we identified common features between mitochondria and vacuolar/lysosomal death pathways in yeast and mammals, contributing to the recognition that RCD is highly conserved. Specifically, we found a novel process contributing to apoptotic cell death in yeast associated with the release of the vacuolar protease Pep4p, the yeast cathepsin D orthologue, and that we later validated in mammalian cells, leading to the proposal of a novel role for this protease in colorectal carcinoma. In another recent study, stemming from previous studies with yeast, we identified the plasmmalemal V-ATPase of highly metastatic cells as the molecular target of lactoferrin, which underlies its selectivity against highly metastatic cells, allowing a more rational use of this natural compound in cancer therapy.
These are 2 major breakthroughs which illustrate the potential of the yeast model to unveil novel roles of a cell death regulator and the mechanism of action of an antitumoral compound, and which fuel innovation in the design of new therapeutic strategies for diseases associated with deficient cell death mechanisms, such as cancer.
References
Pereira C et al. (2010). Mitochondrial degradation in acetic acid-induced yeast apoptosis: the role of Pep4 and the ADP/ATP carrier. Molecular Microbiology, 76: 1398-1410. DOI: 10.1111/j.1365-2958.2010.07122
Oliveira CSF et al. (2015) Cathepsin D protects colorectal cancer cells from acetate-induced apoptosis through autophagy-independent degradation of damaged mitochondria. Cell Death Dis.18;6:e1788. DOI: 10.1038/cddis.2015.157
Pereira C et al. (2016). Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase. Oncotarget, 7 (28): 62144-62158. DOI: 10.18632/oncotarget.11394
Manuela Côrte-Real
Head of the Cell Death Research Group
Centro de Biologia Molecular e Ambiental
Universidade do Minho
mcortereal@bio.uminho.pt
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