Vemurafenib activates the sonic hedgehog pathway and promotes thyroid cancer stem cell self-renewal.

IF 4.1 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Endocrine-related cancer Pub Date : 2023-09-27 Print Date: 2023-11-01 DOI:10.1530/ERC-22-0392

Yurong Lu, Yuqing Zhao, Penggang Liu, Xiulong Xu

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引用次数: 0

Abstract

B-Raf kinase inhibitors such as vemurafenib (PLX4032) and dabrafenib have limited therapeutic efficacy on BRAF-mutated thyroid cancer. Cancer stem cells (CSCs) play important roles in tumor recurrence, drug resistance, and metastasis. Whether CSCs play a role in dampening the antitumor activity of B-Raf kinase inhibitors remains unknown. Here, we report that vemurafenib (PLX4032) induced the expression of several stemness-related genes including Gli1, Snail, BMI1, and SOX2 in two anaplastic thyroid cancer cell lines, SW1736 and 8505C, but decreased the expression of these genes in A375 cells, a human melanoma cell line. PLX4032 promoted thyroid cancer stem cell self-renewal, as evidenced by increased numbers of aldehyde dehydrogenase-positive cells and thyrospheres. Mechanistically, PLX4032 activates the PI-3 and mitogen-activated protein kinase pathways through HER3 to cross-activate Gli1, a transcription factor of the sonic hedgehog (Shh) pathway. GANT61, a specific inhibitor of Gli1, blocked the expression of the stemness-related genes in PLX4032-treated thyroid cancer cells in vitro and in vivo in two thyroid cancer xenograft models. GANT61 treatment alone weakly inhibited SW1736 tumor growth but enhanced the antitumor activity of PLX4032 when used in combination. Our study provides mechanistic insights into how thyroid cancer poorly responds to B-Raf kinase inhibitors and suggests that targeting B-Raf and the Shh pathway in combination may overcome thyroid cancer drug resistance.

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Vemurafenib激活声波hedgehog通路，促进甲状腺癌症干细胞自我更新。

B-Raf激酶抑制剂，如vemurafenib（PLX4032）和dabrafenib对BRAF突变的甲状腺癌症的治疗效果有限。癌症干细胞（CSCs）在肿瘤复发、耐药和转移中起着重要作用。CSC是否在抑制B-Raf激酶抑制剂的抗肿瘤活性中发挥作用尚不清楚。在此，我们报道了vemurafenib（PLX4032）在两种间变性甲状腺癌症细胞系SW1736和8505C中诱导了包括Gli1、Snail、BMI1和SOX2在内的几种干细胞相关基因的表达，但在A375细胞（一种人类黑色素瘤细胞系）中降低了这些基因的表达。PLX4032促进了甲状腺癌症干细胞的自我更新，醛脱氢酶阳性细胞和甲状腺球数量的增加证明了这一点。从机制上讲，PLX4032通过HER3激活PI-3和促分裂原活化蛋白激酶途径，以交叉激活Gli1，一种声音刺猬（Shh）途径的转录因子。GANT61是Gli1的特异性抑制剂，在两种甲状腺癌症异种移植模型中，在体外和体内阻断PLX4032治疗的甲状腺癌症细胞中干细胞相关基因的表达。单独的GANT61治疗弱地抑制SW1736肿瘤生长，但当联合使用时增强了PLX4032的抗肿瘤活性。我们的研究为癌症对B-Raf激酶抑制剂的不良反应提供了机制上的见解，并表明联合靶向B-Raf和Shh途径可以克服甲状腺癌症耐药性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Endocrine-related cancer 医学-内分泌学与代谢

CiteScore

7.80

自引率

2.60%

发文量

138

审稿时长

6-12 weeks

期刊介绍： Endocrine-Related Cancer is an official flagship journal of the Society for Endocrinology and is endorsed by the European Society of Endocrinology, the United Kingdom and Ireland Neuroendocrine Society, and the Japanese Hormones and Cancer Society. Endocrine-Related Cancer provides a unique international forum for the publication of high quality original articles describing novel, cutting edge basic laboratory, translational and clinical investigations of human health and disease focusing on endocrine neoplasias and hormone-dependent cancers; and for the publication of authoritative review articles in these topics. Endocrine neoplasias include adrenal cortex, breast, multiple endocrine neoplasia, neuroendocrine tumours, ovary, prostate, paraganglioma, parathyroid, pheochromocytoma pituitary, testes, thyroid and hormone-dependent cancers. Neoplasias affecting metabolism and energy production such as bladder, bone, kidney, lung, and head and neck, are also considered.