Glucose Restriction Combined with Autophagy Inhibition and Chemotherapy in HCT 116 Spheroids Decreases Cell Clonogenicity and Viability Regulated by Tumor Suppressor Genes.
Glucose Restriction Combined with Autophagy Inhibition and Chemotherapy in HCT 116 Spheroids Decreases Cell Clonogenicity and Viability Regulated by Tumor Suppressor Genes.
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DOI：
10.1021/acs.jproteome.7b00293
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发表时间：
2017-08-04
影响因子：
4.4
通讯作者：
Hummon AB
中科院分区：
文献类型：
--
作者：
Schroll MM;LaBonia GJ;Ludwig KR;Hummon AB
耐药是一种普遍的现象，它会降低癌症治疗的疗效，并导致癌症的进展和转移。化疗前削弱耐药癌细胞是对抗化疗耐药的潜在策略。破坏耐药癌细胞的一种方法是调节营养摄入。营养限制与靶向复合治疗的结合导致明显的分子变化。该研究为在结直肠癌细胞中同时限制葡萄糖和抑制自噬来增强现有的化疗方案提供了有价值的信息。在这项研究中，我们利用全球定量蛋白质组学和成像质谱技术探索了驱动细胞对营养限制、自噬抑制和伊立替康化疗反应的化学途径。我们确定了重要的途径被改变，包括自噬和糖酵解、糖异生和蔗糖降解的代谢。我们还发现，周期生物钟2 (PER2)，一种肿瘤抑制蛋白，只有在自噬抑制和化疗限制葡萄糖时才显著上调。这些差异调控途径的上游调控因子被确定与癌症有关，显示出肿瘤抑制蛋白的增加和核蛋白1 （NUPR1）的减少，NUPR1是化疗耐药的重要蛋白。我们还评估了这些细胞的表型反应，发现自噬抑制和化疗增加了细胞凋亡，降低了细胞的克隆原性和活力。当葡萄糖限制联合自噬抑制和化疗时，所有表型结果都增强。总之，我们的研究结果表明，葡萄糖代谢在癌细胞生存化疗的能力中起着重要作用。在化疗前通过葡萄糖限制和自噬抑制来削弱癌细胞，癌细胞对治疗变得更加敏感。
Drug resistance is a prevalent phenomenon that decreases the efficacy of cancer treatments and contributes to cancer progression and metastasis. Weakening drug resistant cancer cells prior to chemotherapy is a potential strategy to combat chemoresistance. One approach to damage resistant cancer cells is modulation of nutritional intake. The combination of nutrient restriction with targeted compound treatment results in pronounced molecular changes. This study provides valuable information about augmenting existing chemotherapeutic regimes with simultaneous glucose restriction and autophagy inhibition in colorectal cancer cells. In this study, we explore the chemical pathways that drive the cellular response to nutrient restriction, autophagy inhibition and the chemotherapy irinotecan using global quantitative proteomics and imaging mass spectrometry. We determined that significant pathways were altered including autophagy and metabolism via glycolysis, gluconeogenesis, and sucrose degradation. We also found that period circadian clock 2 (PER2), a tumor suppressor protein, was significantly up regulated only when glucose was restricted with autophagy inhibition and chemotherapy. The upstream regulators of these differentially regulated pathways were determined to have implications in cancer, showing an increase of tumor suppressor proteins and a decrease in nuclear protein 1 (NUPR1) an important protein in chemoresistance. We also evaluated the phenotypic response of these cells and discovered autophagy inhibition and chemotherapy treatment increased apoptosis and decreased cell clonogenicity and viability. When glucose restriction was combined with autophagy inhibition and chemotherapy, all of the phenotypic results were intensified. In sum, our results indicate that glucose metabolism is of great importance in the ability of cancer cells to survive chemotherapy. By weakening cancer cells with glucose restriction and autophagy inhibition prior to chemotherapy, cancer cells become more sensitive to therapy.
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影响因子：
4.1
作者：
Beger RD
通讯作者：
Beger RD
影响因子：
24.3
作者：
Lee, Changhan;Raffaghello, Lizzia;Longo, Valter D.
通讯作者：
Longo, Valter D.
影响因子：
7.5
作者：
Liang X;Tang J;Liang Y;Jin R;Cai X
通讯作者：
Cai X
影响因子：
7.4
作者：
Liu X;Hummon AB
通讯作者：
Hummon AB
DOI：
10.1007/s13361-014-1071-0
发表时间：
2015-04-01
影响因子：
3.2
作者：
Liu, Xin;Hummon, Amanda B.
通讯作者：
Hummon, Amanda B.