Differentiation-inducing factor (DIF) is one of a class of effector molecules that induce changes in cell chemistry, inhibiting growth and promoting differentiation of cell type. This name has been given to several factors before it was clear if they were the same or different effectors. More recently DIFs have garnered interest with their potential tumor inhibiting properties. [1] DIFs have also been used to help regulate plant growth.
Dictyostelium discoideum has been used since the 1940s to study cellular and developmental biology. [2] It is well-suited for this research because it only develops two types of cells (stalk and spore) during morphogenesis. Each cell type has a distinct physical origin within the organism; pre-stalk cells coming from the anterior side and pre-spore cells from the posterior. Early evidence showed the differentiation of dense patches of pre-stalk cells were induced by cyclic AMP (cAMP) along with "a factor" that was likely low in molecular weight and able to diffuse across membranes. [3] The structures for DIF-1, DIF-2, and DIF-3 were identified as these factors for stalk differentiation and subsequently synthesized to further research into implications for developmental biology. [4] [5] DIFs 1-3 are chlorinated hexaphenones (phenylalkan-1-ones, with chloro, hydroxy and methoxy substitution on the benzene ring), and have been isolated from Dictyostelium discoideum slime mold.
Some research has shown that they have a role in controlling chemotaxis of Dictyostelium discoideum , too. DIF-1 and DIF-3 are related in structure and function. DIF-3 is formed from the first step in the breakdown of DIF-1. In this state DIF-3 only performs about 3.5% as much of the activity of its predecessor. DIF-2 is unrelated to DIFs -1 and -3, but it works 40% as well as DIF-1 does to induce differentiation in stalk cells. Despite this similarity in function during differentiation, DIFs -1 and -2 act very differently in chemotactic movement of the cells toward cAMP. DIF-1 has a slight inhibitory effect on movement of starved cells toward cAMP, while DIF-2 has a strong positive effect of movement of these cells toward cAMP. These effects are thought to be carried out through phosphodiesterase activations that impact cGMP production to impact chemotaxis. [6] An increase in chemotaxis can be related to malignant migration of cancer cells.
Investigation into the anti-tumor properties of DIFs have followed one main line; the disruption of a pathway necessary for the cancer's uncontrolled growth reducing its proliferative ability. As mentioned above, the ability of DIF-1 to decrease movement of proliferating cells toward sources of energy could serve as an anti-tumor property. In another example, DIF-1 has been shown to reduce the proliferation of gastric cancer cells via upregulation of the MEK-ERK-dependent pathway. [7] Other studies have shown how complicated the anti-tumor interactions of DIFs may be, especially when considering the indirect impacts DIFs have on target molecules. For instance, DIF-like molecules have been shown to inhibit cell growth and bring about cell death through uncoupling in mitochondria. [8]
More recent focus has been on the potential therapeutic effects DIF-like molecules. Derivatives of DIF-1 and DIF-3 have already been investigated with promising initial results. One group of derivatives yielded two DIF-1-like compounds that were effective in suppression of IL-2 production which could be helpful in controlling septic responses and other infections. [9]
Cyclic adenosine monophosphate is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transduction in many different organisms, conveying the cAMP-dependent pathway.
Slime mold or slime mould is an informal name given to a polyphyletic assemblage of unrelated eukaryotic organisms in the Stramenopiles, Rhizaria, Discoba, Amoebozoa and Holomycota. Most are microscopic; those in the Myxogastria form larger plasmodial slime molds visible to the naked eye. The slime mold life cycle includes a free-living single-celled stage and the formation of spores. Spores are often produced in macroscopic multicellular or multinucleate fruiting bodies which may be formed through aggregation or fusion; aggregation is driven by chemical signals called acrasins. Slime molds contribute to the decomposition of dead vegetation; some are parasitic.
The dictyostelids or cellular slime molds are a group of slime molds or social amoebae.
Dictyostelium is a genus of single- and multi-celled eukaryotic, phagotrophic bacterivores. Though they are Protista and in no way fungal, they traditionally are known as "slime molds". They are present in most terrestrial ecosystems as a normal and often abundant component of the soil microflora, and play an important role in the maintenance of balanced bacterial populations in soils.
C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.
Cell migration is a central process in the development and maintenance of multicellular organisms. Tissue formation during embryonic development, wound healing and immune responses all require the orchestrated movement of cells in particular directions to specific locations. Cells often migrate in response to specific external signals, including chemical signals and mechanical signals. Errors during this process have serious consequences, including intellectual disability, vascular disease, tumor formation and metastasis. An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumour cells.
Anoikis is a form of programmed cell death that occurs in anchorage-dependent cells when they detach from the surrounding extracellular matrix (ECM). Usually cells stay close to the tissue to which they belong since the communication between proximal cells as well as between cells and ECM provide essential signals for growth or survival. When cells are detached from the ECM, there is a loss of normal cell–matrix interactions, and they may undergo anoikis. However, metastatic tumor cells may escape from anoikis and invade other organs.
Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:
Chelerythrine is a benzophenanthridine alkaloid present in the plant Chelidonium majus. It is a potent, selective, and cell-permeable protein kinase C inhibitor in vitro. And an efficacious antagonist of G-protein-coupled CB1 receptors. This molecule also exhibits anticancer qualities and it has served as a base for many potential novel drugs against cancer. Structurally, this molecule has two distinct conformations, one being a positively charged iminium form, and the other being an uncharged form, a pseudo-base.
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell.
B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.
Each species of slime mold has its own specific chemical messenger, which are collectively referred to as acrasins. These chemicals signal that many individual cells aggregate to form a single large cell or plasmodium. One of the earliest acrasins to be identified was cyclic AMP, found in the species Dictyostelium discoideum by Brian Shaffer, which exhibits a complex swirling-pulsating spiral pattern when forming a pseudoplasmodium.
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.
Radiation-inducible immediate-early gene IEX-1 is a protein that in humans is encoded by the IER3 gene.
Dictyostelium discoideum is a species of soil-dwelling amoeba belonging to the phylum Amoebozoa, infraphylum Mycetozoa. Commonly referred to as slime mold, D. discoideum is a eukaryote that transitions from a collection of unicellular amoebae into a multicellular slug and then into a fruiting body within its lifetime. Its unique asexual life cycle consists of four stages: vegetative, aggregation, migration, and culmination. The life cycle of D. discoideum is relatively short, which allows for timely viewing of all stages. The cells involved in the life cycle undergo movement, chemical signaling, and development, which are applicable to human cancer research. The simplicity of its life cycle makes D. discoideum a valuable model organism to study genetic, cellular, and biochemical processes in other organisms.
Chemorepulsion is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated. The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.
Bacillus subtilis is a rod-shaped, Gram-positive bacteria that is naturally found in soil and vegetation, and is known for its ability to form a small, tough, protective and metabolically dormant endospore. B. subtilis can divide symmetrically to make two daughter cells, or asymmetrically, producing a single endospore that is resistant to environmental factors such as heat, desiccation, radiation and chemical insult which can persist in the environment for long periods of time. The endospore is formed at times of nutritional stress, allowing the organism to persist in the environment until conditions become favourable. The process of endospore formation has profound morphological and physiological consequences: radical post-replicative remodelling of two progeny cells, accompanied eventually by cessation of metabolic activity in one daughter cell and death by lysis of the other.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
N2a cells are a fast-growing mouse neuroblastoma cell line.
HL156A is a derivative of metformin and a potent oxidative phosphorylation inhibitor and AMP-activated protein kinase activating biguanide. Certain types of cancer cells requires oxidative phosphorylation to survive. By targeting it, HL156A might help in improving anticancer therapy. It is more potent than acadesine or metformin at activating AMP-activated protein kinase. It is synthesized by Hanall Biopharma.