Author: Brandon Copping
Cancer is a disease that takes the lives of millions of people worldwide each year1. As such, research into its causes and mechanisms of action has been a top priority of medical science for decades. The main issue with cancer is that every variant of the disease begins under a very different set of conditions than every other kind. In essence, this makes find a solution to battle every type of cancer akin to finding one cure for hundreds of diseases that, though on the surface seem very similar in nature, are in fact wholly different beasts. Since cancer is, in the simplest terms, a disease of cell proliferation gone too far, fighting it is very tricky since the treatment has to stop the cancer cells from dividing without impacting healthy cell division enough to cause significant harm. However, there are notable differences between healthy cells and oncogenic cells, and that is something anticancer pharmaceutical research can capitalize on. In a 2017 paper published in Nature by Keckesova et al., a possible tumor-suppressing mitochondrial protein called LACTB is discovered.2 What makes this protein so groundbreaking is that when production is induced there is significantly decreased proliferation in metastatic breast cancer cells to the extent that some tumors completely apoptosed within little more than a month. If this turns out to be a viable treatment method for human cancers it would completely revolutionize cancer treatments since patients could be cancer-free within weeks of treatment initiation.
In order to address what the authors described as a largely unexplored area of cancer research, the authors decided to take a look at gene expression in cells where cancer rates are very low, for example heart and brain cells. Once they found which genes had significantly higher expression in the more non-tumorigenic cell types, they settled on five genes to test: LACTB, SMPX, CAP2, REEP1, and PDLIM3. Only overexpression of the LACTB gene showed a significant enough decline in proliferation ability when induced in tumorigenic cells that were also induced with a known oncogene. Up until this point, LACTB was thought to have a role in regulating metabolic processes in the mitochondria as well as regulate complex I of the electron transport chain. However, its role in reducing proliferation of cancerous cells was still unknown, since its expression was downregulated in around 40% of tested breast cancer tissues and there seemed to be no correlation between this downregulation and tumor type or size.
To test what kind of effects inducing expression of LACTB had in breast cancer cells, the team created a system in the cells in which the LACTB gene would be activated upon exposure to doxycycline, a common antibiotic used to treat bacteria and protozoan infection that has also previously been shown to have effects on mitochondrial translation.3 When induced, LACTB caused cells to withdraw from the cell cycle. Unfortunately, this did not happen in all breast cancer cell lines, however it did negatively affect proliferation in a significant majority of them thereby showing its usefulness as a possibly promising treatment in the future. Despite this, the exact function of LACTB was still not known, so the authors performed further experiments in order to elucidate what cellular role this protein played.
The first of these experiments was to determine if the reverse of LACTB’s proliferation hindering effects was true. In order to determine this, the team used short hairpin RNA (shRNA) to knockdown LACTB expression and see if that was enough to induce tumorigenesis. Surprisingly, near complete knockdown of LACTB also had the proliferation-reducing effect leading the authors to conclude that some amount of LACTB is necessary for efficient proliferation. However, once a known oncogene was also induced in the cell, tumors began to form. This shows that knockdown of LACTB on its own is not enough to cause tumorigenesis in breast cancer cell lines. Additionally, induction of LACTB caused a shift in cell marker expression in the cancer lines away from mesenchymal and cancer stem cell markers towards expressing more epithelial markers. There was no such change in non-cancerous cell lines. Since previous research had shown that LACTB was involved in some way in fatty acid metabolism4, the authors analyzed mitochondrial lipid levels in cells with induced LACTB expression and found a significant decrease in both lysophosphatidylethanolamines (LPEs) and phosphatidylethanolamines (PEs), two types of lipids that are part of the cell membrane and also play an important role in cell division.5 To see if the reduction in these lipids were the cause of the reduced proliferation, they supplied exogenous LPE to the cells, since extracellular PE cannot be transported, which allowed the cells to intake it and transform some of it into PE. This allowed the cells to resume proliferation as they had before and helped show that is was very likely the lowered production of these lipids that caused the decrease in proliferation in cancerous cell lines. In order to find the cause of the reduced creation of these lipids, the authors investigated what downstream effects induction of LACTB might be having. Upon doing this, they discovered that the protein phosphatidylserine decarboxylase (PISD), which converts phosphatidylserine (PS) into PE, had significantly reduced activity when LACTB expression was induced. Further investigation into the properties of LACTB prompted the authors to hypothesize that LACTB possesses proteolytic activity and therefore may be physically cleaving PISD before it has the opportunity to convert PS into PE. However, in vivo experiments showed no significant direct interaction between LACTB and PISD so the exact mechanism of action is still largely unknown.
Given how prominent cancer is in the minds of many people in modern society, finding ways to combat it that would eliminate it without significant side effects is incredibly important. In this paper, we see a possible method for increasing expression of a protein already existing within the body that in most cases has a deleterious effect on cancer cell proliferation while having little to no negative effect on healthy cells. This makes LACTB induction a prime candidate for becoming a possible cancer treatment in the future.
Link to paper: https://www.ncbi.nlm.nih.gov/pubmed/28329758
- Keckesova Z, et al. LACTB is a tumour suppressor that modulates lipid metabolism and cell state. Nature 543, 681-686 (2017).
- Ahler, E. et al. Doxycycline alters metabolism and proliferation of human cell lines. PLoS One 8, (2013).
- Yang, X. et al. Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat. Genet. 41, 415–423 (2009).
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