Marín-Hernández Alvaro, Gallardo-Pérez Juan C, Ralph Stephen J, Rodríguez-Enríquez Sara, Moreno-Sánchez Rafael
Instituto Nacional de Cardiología, Departamento de Bioquímica, Juan Badiano No. 1, Sección XVI, Tlalpan, México D.F. 14080, Mexico.
Mini Rev Med Chem. 2009 Aug;9(9):1084-101. doi: 10.2174/138955709788922610.
To develop new and more efficient anti-cancer strategies it will be important to characterize the products of transcription factor activity essential for tumorigenesis. One such factor is hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor induced by low oxygen conditions and found in high levels in malignant solid tumors, but not in normal tissues or slow-growing tumors. In fast-growing tumors, HIF-1alpha is involved in the activation of numerous cellular processes including resistance against apoptosis, over-expression of drug efflux membrane pumps, vascular remodeling and angiogenesis as well as metastasis. In cancer cells, HIF-1alpha induces over-expression and increased activity of several glycolytic protein isoforms that differ from those found in non-malignant cells, including transporters (GLUT1, GLUT3) and enzymes (HKI, HKII, PFK-L, ALD-A, ALD-C, PGK1, ENO-alpha, PYK-M2, LDH-A, PFKFB-3). The enhanced tumor glycolytic flux triggered by HIF-1alpha also involves changes in the kinetic patterns of expressed isoforms of key glycolytic enzymes. The HIF-1alpha induced isoforms provide cancer cells with reduced sensitivity to physiological inhibitors, lower affinity for products and higher catalytic capacity (Vmax(f)) in forward reactions because of marked over-expression compared to those isoforms expressed in normal tissues. Some of the HIF1alpha-induced glycolytic isoforms also participate in survival pathways, including transcriptional activation of H2B histone (by LDH-A), inhibition of apoptosis (by HKII) and promotion of cell migration (by ENO-alpha). HIF-1alpha action may also modulate mitochondrial function and oxygen consumption by inactivating the pyruvate dehydrogenase complex in some tumor types, or by modulating cytochrome c oxidase subunit 4 expression to increase oxidative phosphorylation in other cancer cell lines. In this review, the roles of HIF-1alpha and HIF1alpha-induced glycolytic enzymes are examined and it is concluded that targeting the HIF1alpha-induced glucose transporter and hexokinase, important to glycolytic flux control, might provide better therapeutic targets for inhibiting tumor growth and progression than targeting HIF1alpha itself.
为了开发新的、更有效的抗癌策略，表征肿瘤发生所必需的转录因子活性产物将很重要。其中一个这样的因子是缺氧诱导因子-1α（HIF-1α），它是一种由低氧条件诱导的转录因子，在恶性实体瘤中含量很高，但在正常组织或生长缓慢的肿瘤中则不然。在快速生长的肿瘤中，HIF-1α参与多种细胞过程的激活，包括抗凋亡、药物外排膜泵的过度表达、血管重塑和血管生成以及转移。在癌细胞中，HIF-1α诱导几种糖酵解蛋白异构体的过度表达和活性增加，这些异构体与非恶性细胞中的不同，包括转运蛋白（GLUT1、GLUT3）和酶（HKI、HKII、PFK-L、ALD-A、ALD-C、PGK1、ENO-α、PYK-M2、LDH-A、PFKFB-3）。由HIF-1α触发的肿瘤糖酵解通量增强还涉及关键糖酵解酶表达异构体动力学模式的变化。HIF-1α诱导的异构体使癌细胞对生理抑制剂的敏感性降低，对产物的亲和力降低，并且由于与正常组织中表达的异构体相比明显过度表达，在前向反应中具有更高的催化能力（Vmax(f)）。一些HIF1α诱导的糖酵解异构体也参与存活途径，包括H2B组蛋白的转录激活（由LDH-A）、凋亡抑制（由HKII）和细胞迁移促进（由ENO-α）。HIF-1α的作用还可能通过在某些肿瘤类型中使丙酮酸脱氢酶复合物失活，或通过调节细胞色素c氧化酶亚基4的表达以增加其他癌细胞系中的氧化磷酸化来调节线粒体功能和氧消耗。在本综述中，研究了HIF-1α和HIF1α诱导的糖酵解酶的作用，并得出结论，靶向对糖酵解通量控制很重要的HIF1α诱导的葡萄糖转运蛋白和己糖激酶，可能比靶向HIF1α本身提供更好的抑制肿瘤生长和进展的治疗靶点。
