AKR1B10 对乳腺癌细胞糖酵解-脂质合成代谢通路的调控作用及机制的研究

Breast cancer is a leading cause of cancer death in women worldwide, accounting for 458,000 deaths annually. Targeted therapies, such as tamoxifen for estrogen receptor (ER)-positive tumors, have improved the clinical outcomes, but drug resistance and disease relapse occur often. Furthermore, triple negative breast cancers are not responsive to the current targeted therapies. Therefore, it is an urgent need to explore new therapeutic targets and develp novel targeted therapies. Our preliminary data show that aldo-keto reductase 1B10 (AKR1B10) is overexpressed in breast cancer and promotes tumor growth and lymphatic metastasis,leading to worse survival of patients. We hypothesize that AKR1B10 may stimulate the glycolysis and lipogenesis in breast cancer cells, promoting cell growth and proliferation. In this study, we will use AKR1B10-expressed or silenced breast cancer cell lines to test this hypothesis. We will study the effect of AKR1B10 on celllular metabolites that regulates allosteric enzymes in energetic metaboilsm, investigate the effect of AKR1B10 on AMPK phosphorylation and the energetic metabolic pathway, and define the role of AKR1B10 in regulating MAPK/ERK signaling pathway. The study results will define the role and molecular mechanisms of AKR1B10 in regulating glycolysis and lipogenesis in breast cancer cells, providng supportive evidence for AKR1B10 as a new target for breat cancer treatment.

乳腺癌是女性最常见的恶性肿瘤。靶向治疗是目前治疗乳腺癌最有效的手段，但肿瘤抗药性和复发普遍存在，且不适应于三阴乳腺癌。因此，急需研发靶向新标识的治疗。我们前期发现醛酮还原酶1B10（AKR1B10）在乳腺癌组织中高表达，并促进乳腺癌生长和淋巴结转移，与临床不良预后相关，提示其作为治疗新靶标的可能性。AKR1B10促乳腺癌作用可能与其激活癌细胞内糖酵解与脂质合成代谢有关。本研究拟利用前期建立的转AKR1B10及AKR1B10沉默乳腺癌细胞系，通过探讨：①AKR1B10对乳腺癌细胞内糖酵解別位调节物水平的影响；②AKR1B10对乳腺癌细胞AMPK磷酸化活性及其能量代谢调节通路的影响；③AKR1B10对MAPK/ERK信号通路的调节作用，阐明其在调控乳腺癌细胞内糖酵解-脂质合成代谢中的作用及其机制。从而为AKR1B10作为乳腺癌治疗新靶标的可行性提供科学依据。

乳腺癌是女性最常见的恶性肿瘤。靶向治疗是目前治疗乳腺癌最有效的手段，但肿瘤抗药性和复发普遍存在，且不适应于三阴乳腺癌。因此，急需研发靶向新标识的治疗。我们前期发现醛酮还原酶1B10（AKR1B10）在乳腺癌组织中高表达，并促进乳腺癌生长和淋巴结转移，与临床不良预后相关，提示其作为治疗新靶标的可能性。AKR1B10促乳腺癌作用可能与其激活癌细胞内糖酵解与脂质合成代谢有关。本研究拟利用前期建立的转AKR1B10及AKR1B10沉默乳腺癌细胞系，通过探讨：①AKR1B10对乳腺癌细胞内糖酵解別位调节物水平的影响；②AKR1B10 对乳腺癌细胞AMPK磷酸化活性及其能量代谢调节通路的影响；③AKR1B10对 MAPK/ERK信号通路的调节作用，阐明其在调控乳腺癌细胞内糖酵解-脂质合成代谢中的作用及其机制。从而为AKR1B10作为乳腺癌治疗新靶标的可行性提供科学依据。