PubMed · 14220989
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E A LOEBBECKE. 1964. [MUTATION GENETICS].. https://pubmed.ncbi.nlm.nih.gov/14220989/
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Ceramides, which are produced from the hydrolysis of sphingomyelin or synthesized from serine and palmitate in a de novo pathway, are regarded as important cellular signals for inducing apoptosis. However, controversy over this proposed role of ceramides exists. Using stable isotope labelling coupled with GC (gas chromatography)-MS and mass isotopomer distribution analysis, we have studied the metabolism of exogenous long-chain ceramides in HL60 cells. Our results do not support the concept of enhanced ceramide transport into cells induced by solvent mixtures of ethanol and hydrocarbons. In addition, cell toxicity does not correlate with the amount of intact ceramide in the cells. Our results are more consistent with a disturbance of sphingomyelin metabolism induced by the solvent mixture. The characteristics of this disturbed sphingolipid disposition are the inhibition of dihydroceramide desaturation and an enhanced degradation of sphingomyelin. As a consequence, dihydroceramides accumulate and the cellular sphingomyelin content decreases. Inhibition of these pathways is most likely to be induced by the increased production of novel ceramide metabolites instead of by intact ceramides. Octadecane-1,2-diol is identified as a possible mediator. Treatments that divert ceramide degradation to the novel pathway are potential strategies in cancer therapy for inducing cell toxicity.
The recognition that the processes involved in tumour formation are strikingly similar to developmental morphogenetic processes, such as gastrulation, has refashioned our approach to cancer research. Wnt and its receptor Frizzled govern the morphogenetic processes of gastrulation. Directed cell movements during gastrulation require the cells to undergo transient epithelial to mesenchymal transitions, enabling the cells to dissociate and migrate. To do this, Frizzleds activate different intracellular signalling cascades that affect cellular processes such as differentiation, proliferation, cell motility and cell polarity. Cell dissociation and migration are also essential for tumour cell invasion and metastases and the frequent deregulation of Wnt and Frizzled in human cancers implicates them in this process. Indeed recent evidence links both canonical (Wnt/beta-catenin) and non-canonical (Wnt/Ca2+) pathways to tumour invasion and metastases, emphasizing the importance of Frizzled in tumour growth and progression.
We have previously shown that the metabolism for most efficient cell growth can be realized by a combination of two types of elementary modes. One mode produces biomass while the second mode generates only energy. The identity of the four most efficient biomass and energy pathway pairs changes, depending on the degree of oxygen limitation. The identification of such pathway pairs for different growth conditions offers a pathway-based explanation of maintenance energy generation. For a given growth rate, experimental aerobic glucose consumption rates can be used to estimate the contribution of each pathway type to the overall metabolic flux pattern. All metabolic fluxes are then completely determined by the stoichiometries of involved pathways defining all nutrient consumption and metabolite secretion rates. We present here equations that permit computation of network fluxes on the basis of unique pathways for the case of optimal, glucose-limited Escherichia coli growth under varying levels of oxygen stress. Predicted glucose and oxygen uptake rates and some metabolite secretion rates are in remarkable agreement with experimental observations supporting the validity of the presented approach. The entire most efficient, steady-state, metabolic rate structure is explicitly defined by the developed equations without need for additional computer simulations. The approach should be generally useful for analyzing and interpreting genomic data by predicting concise, pathway-based metabolic rate structures.