Metabolomics–Proteomics Combined Approach Identifies Differential Metabolism-Associated Molecular Events between Senescence and Apoptosis

Apoptosis
and senescence are two types of cell fates in response
to chemotherapy. Besides canonical pathways that mediate cell fates,
cancer cell metabolism has been revealed as a crucial factor affecting
cell fate decisions and thus represents a new target for antitumor
therapy. Therefore, a comprehensive description of metabolic pathways
underlying cell senescence and apoptosis in response to chemotherapy
is highly demanded for therapeutic exploitation of both processes.
Herein we employed a metabolomics–proteomics combined approach
to identify metabolism-associated molecular events that mediate cellular
responses to senescence and apoptosis using doxorubicin-treated human
breast cancer cells MCF7 as models. Such biomics approach revealed
that tricarboxylic acid cycle, pentose phosphate pathway, and nucleotide
synthesis pathways were significantly upregulated in the senescent
model, whereas fatty acid synthesis was reduced. In apoptotic cells,
an overall reduced activity of major metabolic pathways was observed
except for the arginine and proline pathway. Combinatorially, these
data show the utility of biomics in exploring biochemical mechanism-based
differences between apoptosis and senescence and reveal an unprecedented
finding of the metabolic events that were induced for survival by
facilitating ROS elimination and DNA damage repair in senescent cells,
while they were downregulated in apoptotic cells when DNA damage was
irreparable.

细胞凋亡（Apoptosis）与细胞衰老（senescence）是癌细胞应对化疗的两种细胞命运类型。除介导细胞命运的经典通路外，癌细胞代谢已被证实是影响细胞命运决策的关键因素，因此成为抗肿瘤治疗的全新靶点。故而，全面阐明化疗诱导下细胞衰老与凋亡背后的代谢通路，对于靶向调控这两个过程的治疗开发具有重要价值。本研究采用代谢组学-蛋白质组学（metabolomics–proteomics）联合分析策略，以阿霉素（doxorubicin）处理的人类乳腺癌细胞MCF7（MCF7）为模型，筛选介导细胞衰老与凋亡应答的代谢相关分子事件。该组学分析结果显示，衰老模型细胞中三羧酸循环、磷酸戊糖途径及核苷酸合成通路均显著上调，而脂肪酸合成通路活性则被抑制。在凋亡细胞中，除精氨酸-脯氨酸代谢通路外，主要代谢通路的整体活性均呈现下降趋势。综合来看，本研究数据证实了组学技术在探索细胞凋亡与衰老间基于生化机制的差异方面的应用价值，并揭示了一项前所未有的发现：衰老细胞可通过促进活性氧（ROS）清除与DNA损伤修复来诱导相关代谢事件以维持存活，而当DNA损伤无法修复时，这类代谢事件在凋亡细胞中则会被下调。