Department of Pathology, Dalhousie University, Halifax, NS, Canada.
Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada.
Cell Death Dis. 2018 Sep 24;9(10):990. doi: 10.1038/s41419-018-0997-8.
Cancer cells with a less differentiated stem-like phenotype are more resistant to therapeutic manipulations than their differentiated counterparts, and are considered as one of the main causes of cancer persistence and relapse. As such, induction of differentiation in cancer stem-like cells (CSLCs) has emerged as an alternative strategy to enhance the efficacy of anticancer therapies. CSLCs are metabolically distinct from differentiated cells, and any aberration from the intrinsic metabolic state can induce differentiation of CSLCs. Therefore, metabolism-related molecular targets, with a capacity to promote differentiation within CSLCs, are of therapeutic importance. Here, we demonstrate that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme catalyzing the synthesis of amino acid serine, is important for maintaining the poorly differentiated, stem-like state of CSLCs. Our data shows that PHGDH deficiency impairs the tumorsphere formation capacity in embryonal carcinoma stem-like cells (ECSLCs), breast cancer stem-like cells (BCSLCs) and patient-derived brain tumor-initiating cells (BTICs), which is accompanied by the reduced expression of characteristic stemness-promoting factors, such as Oct4, Nanog, Sox-2, and Bmi-1. Mechanistically, PHGDH deficiency in ECSLCs promotes differentiation to various lineages via degradation of Oct4 and by increasing the stability of differentiation marker β3-tubulin. Furthermore, PHGDH inhibition promotes p-mTOR independent but Beclin-1-dependent autophagy, independent of apoptosis. When studied in combination, the inhibition of both PHGDH and p-mTOR in ECSLCs causes further augmentation of autophagy, and additionally promotes apoptosis, demonstrating the clinical applicability of PHGDH-based manipulations in cancer therapies. Recapitulating these in vitro findings in CSLC models, the intratumoral PHGDH expression in patient-derived tumors is positively correlated with the mRNA levels of stemness factors, especially Oct4, and cancer patients co-expressing high levels of PHGDH and Oct4 display significantly lower survival than those with low PHGDH/Oct4 co-expression. Altogether, this study identifies a clinically-relevant role for PHGDH in the regulation of stemness-differentiation axis within CSLCs.
具有低分化干细胞样表型的癌细胞比分化细胞更能抵抗治疗操作，被认为是癌症持续存在和复发的主要原因之一。因此，诱导癌症干细胞样细胞（CSLCs）分化已成为增强抗癌治疗效果的一种替代策略。CSLCs 在代谢上与分化细胞不同，任何偏离内在代谢状态的因素都可以诱导 CSLCs 的分化。因此，与代谢相关的分子靶点，具有在 CSLCs 中促进分化的能力，具有治疗意义。在这里，我们证明了磷酸甘油酸脱氢酶（PHGDH），一种催化氨基酸丝氨酸合成的必需酶，对于维持 CSLCs 的低分化、干细胞样状态很重要。我们的数据表明，PHGDH 缺乏会损害胚胎癌细胞干细胞样细胞（ECSLCs）、乳腺癌干细胞样细胞（BCSLCs）和患者来源的脑肿瘤起始细胞（BTICs）的肿瘤球形成能力，同时伴随着特征性干细胞促进因子的表达减少，如 Oct4、Nanog、Sox-2 和 Bmi-1。在机制上，PHGDH 在 ECSLCs 中的缺乏通过降解 Oct4 和增加分化标志物β3-微管蛋白的稳定性来促进向各种谱系的分化。此外，PHGDH 缺乏会促进 p-mTOR 非依赖性但 Beclin-1 依赖性自噬，而不依赖于细胞凋亡。当联合研究时，在 ECSLCs 中同时抑制 PHGDH 和 p-mTOR 会进一步增强自噬，并额外促进细胞凋亡，这证明了基于 PHGDH 的操作在癌症治疗中的临床适用性。在 CSLC 模型中重现这些体外发现，患者来源肿瘤中的肿瘤内 PHGDH 表达与干细胞因子的 mRNA 水平呈正相关，尤其是 Oct4，并且共同表达高水平 PHGDH 和 Oct4 的癌症患者的生存率明显低于那些低 PHGDH/Oct4 共表达的患者。总之，这项研究确定了 PHGDH 在 CSLC 中调节干细胞-分化轴方面的临床相关作用。
