Delineating how retinoic acids regulate lipid metabolism in glioblastoma and their resistance mechanisms

摘要 胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤，也是所有癌症中最致命的一种。主要 治疗GBM的挑战是肿瘤细胞对所有种类的治疗迅速产生抗性。而 我们对GBM生物学的部分理解是阐明潜在抗性的主要障碍 机制等我们的实验室最近发现，GBM极大地改变了脂质代谢，以获得足够的脂质 因为它的快速增长。我们发现，固醇调节元件结合蛋白-1（SREBP-1）， 一种控制脂肪酸合成的转录因子，在GBM中高度表达，是肿瘤发生所必需的 增长我们的研究结果最近得到了多个小组的验证，表明SREBP-1在各种疾病中也升高。 其他癌症。然而，脂质代谢的显著改变是否有助于肿瘤抵抗， 完全未知此外，在癌细胞中上调SREBP-1表达的机制仍然存在， 难以捉摸。有趣的是，我们最近发现，全反式维甲酸（ATRA）和13-顺式维甲酸可以显着 在GBM细胞中以剂量依赖性方式降低SREBP-1和脂肪生成酶的表达。这些 维甲酸是治疗急性早幼粒细胞白血病的有效药物，也已用于治疗GBM 和其他实体瘤，但肿瘤耐药性一直非常具有挑战性。迄今为止，他们的抗肿瘤和 耐药机制仍然知之甚少。我们检测了它们的结合伴侣维甲酸的表达， GBM患者组织中的酸性核受体α（RARα），发现其在肿瘤组织中高度表达， 与SREBP-1表达呈正相关，而与患者生存率差呈负相关。 有趣的是，我们的数据进一步表明，13-cis-RA和ATRA治疗显著增加了 肉毒碱棕榈酰转移酶1A（CPT 1A）是脂肪酸进入线粒体进行β-氧化的关键酶 和能源生产。CPT 1A与视黄酸联合治疗的药理学抑制导致 GBM细胞死亡。总之，这些新的初步数据有力地支持了13-顺式-RA 或ATRA可显著改变GBM脂质代谢，促进脂肪酸氧化，支持肿瘤细胞增殖， 生存和抵抗。我们进一步假设维甲酸治疗联合抑制 SREBP-1激活或脂肪酸氧化将有效抑制GBM生长并克服肿瘤抗性。 本研究的目的是确定以前未报道的维甲酸和RARα的作用和机制 脂质代谢调节和GBM生长（目标1），并开发有效的组合方法， 目标GBM（目标2）。这项研究的完成将揭示上调SREBP-1的潜在机制 表达和脂肪生成，为了解抗肿瘤和耐药性提供了很好的见解。 的机制，并确定新的战略，以目标GBM和克服视黄酸耐药性。

ABSTRACT Glioblastoma (GBM) is the most common primary brain tumor and one of the most lethal of all cancers. The main challenge in treating GBM is the quickly developing resistance to all kinds of treatments by tumor cells. Whereas our partial understanding of GBM biology is a major roadblock to elucidate the underlying resistance mechanisms. Our laboratory recently uncovered that GBM greatly alters lipid metabolism to gain sufficient lipids for its rapid growth. We identified that sterol regulatory element-binding protein-1 (SREBP-1), a master transcription factor that controls fatty acid synthesis, is highly expressed in GBM and is essential for tumor growth. Our findings were recently validated by multiple groups showing that SREBP-1 is also elevated in various other cancers. However, whether the dramatically altered lipid metabolism facilitates tumor resistance is completely unknown. Moreover, the mechanism that upregulates SREBP-1 expression in cancer cells remains elusive. Interestingly, we recently found that all-trans retinoic acid (ATRA) and 13-cis-RA could significantly reduce the expression of SREBP-1 and lipogenic enzymes in a dose-dependent manner in GBM cells. These retinoic acids are effective drugs in treating acute promyelocytic leukemia and have also been used to treat GBM and other solid tumors, but tumor resistance has been very challenging. To date, both their antitumor and resistance mechanisms remain poorly understood. We examined the expression of their binding partner, retinoic acid nuclear receptor α (RARα) in GBM patient tissues and found it to be highly expressed in tumor tissues and positively correlated with SREBP-1 expression, while inversely associated with poor patient survival. Interestingly, our data further show that 13-cis-RA and ATRA treatment significantly increased the expression of carnitine palmitoyltransferase 1A (CPT1A), a key enzyme shuttling fatty acids into mitochondria for β-oxidation and energy production. Pharmacological inhibition of CPT1A combined with retinoic acid treatment resulted in marked GBM cell death. Together, these novel preliminary data strongly support the hypothesis that 13-cis-RA or ATRA can significantly alter lipid metabolism in GBM and promote fatty acid oxidation to support tumor cell survival and resistance. We further hypothesize that retinoic acid treatment in combination with suppression of SREBP-1 activation or fatty acid oxidation will effectively inhibit GBM growth and overcome tumor resistance. The goal of this study is to identify the previously unreported roles and mechanisms of retinoic acids and RARα in lipid metabolism regulation and GBM growth (Aim 1), and to develop effective combination approaches to target GBM (Aim 2). Completion of this study will uncover the underlying mechanism upregulating SREBP-1 expression and lipogenesis in GBM, provide great insights into understanding the antitumor and resistance mechanisms of retinoic acids, and identify novel strategies to target GBM and overcome retinoic acid resistance.