Metabolic utilization of exogenous pyruvate by mutant p53 (R175H) human melanoma cells promotes survival under glucose depletion
Metabolic utilization of exogenous pyruvate by mutant p53 (R175H) human melanoma cells promotes survival under glucose depletion
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DOI：
10.4161/cbt.12.7.16566
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发表时间：
2011-10-01
影响因子：
3.6
通讯作者：
Rieber, Manuel
中科院分区：
文献类型：
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作者：
Chavez-Perez, Valery A.;Strasberg-Rieber, Mary;Rieber, Manuel
肿瘤抑制基因p53的显性阴性（DN） p53突变通过使剩余的野生型等位基因失活，部分地促进了人类癌症的进展。由于肿瘤细胞在远离血管化位点生长时面临葡萄糖和生长因子短缺，因此我们使用基因匹配的人类C8161黑色素瘤携带wt p53或肿瘤相关（DN）突变p53 (R175H)，来研究该突变是否影响代谢应激下的生存。代谢限制（在无葡萄糖培养基中加2%血清18小时）诱导wt p53黑色素瘤中凋亡相关的PARP裂解，即使补充2.77 mM丙酮酸或乳酸。突变型p53黑色素瘤对类似的代谢限制具有抗性，只有在葡萄糖消耗同时使用二苯碘（DPI）（一种超氧化物（O-2*(-)）生成的NADPH氧化酶抑制剂）治疗时才出现PARP断裂。dpi介导的突变型p53细胞凋亡被2.77 mM葡萄糖或丙酮酸抵消，但乳酸补充不起作用。在突变型p53 （R175H）细胞中，丙酮酸增加了葡萄糖消耗下的代谢利用和存活。我们的研究结果首次表明，携带p53 （R175H）突变的黑色素瘤细胞增加：(a)葡萄糖消耗下的存活，被nadph氧化酶调节剂如DPI抵消；(b)补充外源性丙酮酸时对DPI的抗性。
Dominant-negative (DN) p53 mutations in the tumor suppressor p53 gene partly contribute to human cancer progression by inactivating the remaining wild type allele. Since tumor cells face glucose and growth factor shortage when growing distant from sites of vascularization, we used genetically-matched human C8161 melanoma harboring wt p53 or a tumor-associated (DN) mutant p53 (R175H), to investigate whether this mutation influences survival under metabolic stress. Metabolic restriction (18 h in glucose-free medium plus 2% serum) induced apoptosis-associated PARP cleavage in wt p53 melanoma, even when supplemented with 2.77 mM pyruvate or lactate. Mutant p53 melanoma were resistant to a comparable metabolic restriction, only showing PARP fragmentation when glucose depletion was accompanied by treatment with diphenylene iodonium (DPI), a NADPH oxidase inhibitor of superoxide (O-2*(-)) generation. DPI-mediated apoptosis in mutant p53 cells was counteracted by 2.77 mM glucose or pyruvate, but not by lactate supplementation. Metabolic utilization and survival under glucose depletion was increased by pyruvate in mutant p53 (R175H) cells. Our results show for the first time that melanoma cells harboring a p53 (R175H) mutation increase: (a) survival under glucose depletion, counteracted by NADPH-oxidase modulators like DPI; (b) resistance to DPI when supplemented with exogenous pyruvate.