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  • Several genetic and biochemical mechanisms

    2020-07-30

    Several genetic and biochemical mechanisms underlying the bioenergetic profiling of tumors have been discovered in the last decade (for review see Hosseini et al., 2017, Obre and Rossignol, 2015), but most of these findings were obtained on established tumors or on mouse models of cancer progression. Indeed, little attention has been given to the bioenergetic profiling of the cancer initiation phase and how it influences further the bioenergetic behavior of tumors. In the present study, we investigated whether metabolic changes could be detected at the initial stages before typical pathological alterations of carcinogenesis occur, the impact of early metabolic changes in skin tumor formation, and whether these changes can be maintained throughout tumor development. Solar ultraviolet B (UVB) radiation is the primary environmental risk factor responsible for the induction of non-melanoma skin cancers (NMSC) including basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), the most common types of human malignancies worldwide. An estimate 5.4 million cases of NMSCs were affecting 3.3 million patients among the US population in 2012 (Rogers et al., 2015). A major deleterious effect of UVB is the induction of well-defined structural alterations in DNA, which, in turn, trigger the DNA damage response (DDR) network. DDR involves sensing the damage and then transducing this signal to downstream effectors that elicit the appropriate responses including repair of DNA damage, cell-cycle delay, senescence, and/or apoptosis (Lagerwerf et al., 2011, Surova and Zhivotovsky, 2013). The ultimate fate of Rottlerin with damaged DNA is, indeed, dependent on the type and extent of damage and DNA repair capacity (Branzei and Foiani, 2008, Surova and Zhivotovsky, 2013). If not repaired or if misrepaired, UVB-induced DNA damage can ultimately contribute to the development of skin cancers.
    Results
    Discussion In addition to contributing to amino acid and lipid biosynthesis, mitochondrial metabolism affects nucleotide biosynthesis. Indeed, many components that contribute to both pyrimidine and purine bases are derived directly or indirectly from mitochondria. Besides glutamine and aspartate, which can be supplied by mitochondria, pyrimidine synthesis requires the activity of the mitochondrial enzyme DHODH, linking cellular respiration and pyrimidine synthesis directly (Ahn and Metallo, 2015). In support of this notion, our results indicate that oxygen consumption rate, reductive glutamine metabolism, pyrimidine synthesis, and efficient repair of DNA damage are all dependent on DHODH activity in irradiated skin (see Figures 4L–4N, 6, and S2A–S2C). While respiration is thought to primarily support ATP production and regeneration of electron acceptors (e.g., NAD+ and FAD+) (Sullivan et al., 2015, Titov et al., 2016), appearance of tumors and rescue of hypersensitivity to UVB in Tfam-ablated mice upon uridine supplementation revealed that respiration is specifically required for nucleotide biosynthesis upon irradiation, highlighting a distinct anabolic role for respiration in this condition. Consistently, it has been shown that pyrimidine nucleotide levels are increased in cells in response to other genotoxic stressors such as chemotherapy agents. This upregulation of pyrimidine biosynthesis could be considered as a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy and to decrease emergence of resistance, as recently proposed for using doxorubicin and LFN as a promising combination therapy in breast cancer (Brown et al., 2017).