Department of Pathology, University Health Network, 200 Elizabeth Street, 11th floor, Toronto, ON, M5G 2C4, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
Endocr Pathol. 2020 Sep;31(3):231-238. doi: 10.1007/s12022-020-09624-3.
Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (n = 42), adrenal cortical adenoma (ACA; n = 50), and normal adrenal cortical tissue samples (n = 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (p < 0.001 and p = 0.014, respectively) or normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (p = 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (p = 0.003) or normal adrenal cortical tissue samples (p = 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (p < 0.001 and p = 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.
代谢重编程是促进癌变的细胞过程。然而，在肾上腺皮质癌（ACC）中，这种过程仍知之甚少。ACC 是一种侵袭性恶性肿瘤，总体预后较差，治疗选择有限。我们通过检查参与葡萄糖代谢的关键蛋白的免疫组化特征，即己糖激酶（HK1）、丙酮酸激酶（PKM1、PKM2）、琥珀酸脱氢酶（SDHB）和磷酸化 S6 核糖体蛋白（pS6），来描绘 ACC 的代谢表型。在 137 例肾上腺皮质组织样本的组织微阵列中，比较了 ACC（n=42）、肾上腺皮质腺瘤（ACA；n=50）和正常肾上腺皮质组织样本（n=45）之间的蛋白表达。与 ACA（p<0.001 和 p=0.014）或正常肾上腺皮质组织样本（p<0.001 和 p<0.001）相比，ACC 中 HK1 和 PKM2 的细胞质表达明显更高。与正常肾上腺皮质组织样本相比，ACA 中 HK1 和 PKM2 的表达也更高（p<0.001 和 p<0.001）。尽管在 ACC、ACA 和正常样本中 PKM1 的表达总体较低，但 ACC 中的 PKM1 表达高于 ACA（p=0.027）。在我们的肾上腺皮质肿瘤队列中，没有观察到细胞质颗粒状 SDHB 表达缺失，并且 ACC 中的细胞质 pS6 表达低于 ACA（p=0.003）或正常肾上腺皮质组织样本（p=0.008）。值得注意的是，HK1 表达与丙酮酸激酶同工型（PKM2 和 PKM1）表达相关（p<0.001 和 p=0.007）。尽管没有进行功能验证，但这项研究提供了进一步的证据，表明代谢重编程和葡萄糖代谢改变可能通过细胞内糖酵解酶的过度表达而发生在 ACC 的一部分中，特别是 HK1 和 PKM2。在未来的研究中，应探索利用 ACC 中重新编程的葡萄糖代谢来开发新的治疗策略。
