H-Ras 诱导 Nrf2-Pin1 相互作用：对乳腺癌进展的影响。

H-Ras induces Nrf2-Pin1 interaction: Implications for breast cancer progression.

机构信息

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea; Department of Molecular Medicine, Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea.

Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.

出版信息

Toxicol Appl Pharmacol. 2020 Sep 1;402:115121. doi: 10.1016/j.taap.2020.115121. Epub 2020 Jul 1.

DOI:10.1016/j.taap.2020.115121

PMID:32621833

Abstract

Aberrant activation of H-Ras is often associated with tumor aggressiveness in breast cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) is a unique enzyme that interacts with phosphorylated serine or threonine of a target protein and isomerizes the adjacent proline residue. Pin1 is prevalently overexpressed in human cancers, and its overexpression correlates with poor prognosis. Nuclear factor E2-related factor 2 (Nrf2) is a master regulator of cellular redox homeostasis. The sustained activation/accumulation of Nrf2 has been observed in many different types of human malignancies, conferring an advantage for growth and survival of cancer cells. The activated form of H-Ras (GTP-H-Ras) is highly overexpressed in human breast cancer tissues. In our present study, silencing of H-Ras decreased the invasiveness of MDA-MB-231 human breast cancer cells and abrogated the interaction between Pin1 and Nrf2 in these cells. Pin1 knockdown blocked the accumulation of Nrf2, thereby suppressing proliferation and clonogenicity of MCF10A-Ras human mammary epithelial cells. We found that Pin1 binds to Nrf2 which stabilizes this transcription factor by hampering proteasomal degradation. In conclusion, H-Ras activation in cooperation with the Pin1-Nrf2 complex represents a novel mechanism underlying breast cancer progression and constitutive activation of Nrf2 and can be exploited as a therapeutic target.

摘要

H-Ras 的异常激活通常与乳腺癌的肿瘤侵袭性有关。肽基脯氨酰顺反异构酶 NIMA 相互作用 1（Pin1）是一种独特的酶，它与靶蛋白的磷酸化丝氨酸或苏氨酸相互作用，并使相邻脯氨酸残基异构化。Pin1 在人类癌症中广泛过表达，其过表达与预后不良相关。核因子 E2 相关因子 2（Nrf2）是细胞氧化还原平衡的主要调节剂。在许多不同类型的人类恶性肿瘤中观察到 Nrf2 的持续激活/积累，为癌细胞的生长和存活提供了优势。在人类乳腺癌组织中，激活形式的 H-Ras（GTP-H-Ras）高度过表达。在本研究中，沉默 H-Ras 降低了 MDA-MB-231 人乳腺癌细胞的侵袭性，并阻断了这些细胞中 Pin1 和 Nrf2 之间的相互作用。Pin1 敲低阻断了 Nrf2 的积累，从而抑制 MCF10A-Ras 人乳腺上皮细胞的增殖和集落形成。我们发现 Pin1 与 Nrf2 结合，通过阻碍蛋白酶体降解来稳定这种转录因子。总之，H-Ras 的激活与 Pin1-Nrf2 复合物的协同作用代表了乳腺癌进展和 Nrf2 组成性激活的新机制，可作为治疗靶点加以利用。