The Cancer Physiology Project has focused on the biological impact of the metabolic microenvironment of cancer cells and tissues on tumor formation and progression. The aim of the Project is to clarify the molecular basis of cancer specific machineries regulating metabolic events and to apply the unraveled mechanisms to the development of novel and rationale anti-cancer strategies.
Austerity, which is resistance to nutrient starvation, is a characteristic feature of various cancer cells. Due to the high energetic demands of cancer cells and insufficient blood supply to growing tumor tissues, nutrient supply to cancer cells is limited. Austerity provides cancer cells the advantage of surviving under such harsh conditions. Thus, targeting austerity is a promising new strategy for cancer treatment. A series of compounds obtained from plants employed for traditional medicine demonstrated preferential toxicity against pancreatic cancer-derived cells in a nutrient-deprived medium (122, 123, 124, 125). Kigamicin D, one of the anti-austeric compounds previously identified in this project, induced necrosis in melphalan-resistant myeloma cell lines, but showed no toxicity in normal lymphocytes, suggesting its therapeutic potential against drug-resistant intractable multiple myeloma (126).
Hypoxia is another characteristic tumor microenvironment and is known to induce the expression of genes encoding various enzymes regulating energy metabolism. Furthermore, cells capitalize on specific alternative splice variants of these genes to adapt their metabolism to hypoxia. Novel hypoxia-induced splice variants of the genes encoding glycolysis regulating enzymes 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase-3 (PFKFB-3) and PFKFB-4 were identified (127, 128).
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key enzyme regulating cellular and organismal energy metabolism. According to the similarity of the structure of the Ser/Thr kinase domain, 16 kinases have been designated as AMPK-related kinases. However, the physiological functions of many of these kinases remain unclear. SNARK (SNF-1/AMPK-related kinase) is a member of the AMPK-related kinases. A functional nuclear localization signal was identified in its N-terminus, and constitutive nuclear localization of SNARK was observed. Snark influenced transcriptional regulation and this ability was dependent on SNARK nuclear localization (129). Snark-deficient mice exhibited mature-onset obesity accompanied by symptoms similar to those of human metabolic syndrome such as dyslipidemia and glucose intolerance. Furthermore, susceptibility to chemical carcinogen-induced colorectal tumorigenesis was remarkably increased, and such susceptibility correlated with body weight. The above-mentioned findings suggest the importance of SNARK both in tumorigenesis and organismal metabolic regulation, and that Snark-deficient mice are a useful animal model for investigating the relevance of metabolic disorders and tumorigenesis (130).
Effective doses of ionizing radiation during preoperative radiotherapy occasionally cause wound complications after surgery. Using a rat skin model, the usefulness of granulocyte colony-stimulating factor, macrophage colony-stimulating factor and transforming growth factor-beta 1 receptor kinase inhibitors for ameliorating radiation-impaired wound healing was revealed (131).
Although p53 has been extensively characterized as a tumor suppressor, it has been more difficult to determine whether another family member, namely, p73 plays a similar role. Previous in vitro and in vivo models have been hampered to answer this question due to the complicated structure and function of the p73 gene. Even from an identical locus, p73 isoforms expressed from different promoters function oppositely, that is, TAp73 activates the transcription of downstream genes, whereas DNp73 acts as dominant negative for TAp73 and p53. A newly developed TAp73-specific gene-targeted mouse model resolved the problem. TA-p73 null mice were born normally but developed spontaneous and carcinogen-induced tumors. In addition, cells from TAp73 null mice demonstrated genetic instability associated with enhanced aneuploidy, which may account for the increased incidence of spontaneous tumors. Hence, TAp73 exerts tumor-suppressive functions and maintains genetic stability (132).
● K. Tsuchihara ●
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