A pyrrole-based natural small molecule mitigates HSP90 expression in MDA-MB-231 cells and inhibits tumor angiogenesis in mice by inactivating HSF-1
A pyrrole-based natural small molecule mitigates HSP90 expression in MDA-MB-231 cells and inhibits tumor angiogenesis in mice by inactivating HSF-1
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DOI：
10.1007/s12192-017-0802-0
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发表时间：
2017-09-01
影响因子：
3.8
通讯作者：
Aparna, H. S.
中科院分区：
文献类型：
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作者：
Rashmi, K. C.;Atreya, H. S.;Aparna, H. S.
热休克蛋白（HSP）是一种分子伴侣，对癌细胞的生存、增殖、迁移和肿瘤血管生成有重要作用。肿瘤细胞被认为对热休克蛋白“上瘾”。由于转录因子热休克因子1（HSF-1）的上调，热休克蛋白在许多癌症中过表达，热休克因子1是热休克反应的多方面主调节因子。因此，通过HSF-1药理学靶向HSP是治疗恶性肿瘤如三阴性乳腺癌的有效策略。在本研究中，我们评估了吡咯衍生物[双（2-乙基己基）1H-吡咯-3，4-二羧酸酯]，TCCP，从青果叶纯化的抑制热休克反应和血管生成的能力，使用MDA-MB-231细胞和小鼠乳腺癌：埃利希腹水肿瘤模型的功效。TCCP通过灭活HSF-1下调HSP 90，从而抑制肿瘤细胞增殖，VEGF诱导的细胞迁移，并伴随肿瘤负荷和体内新血管生成的减少。HSPs的抑制机制涉及PI 3 K/Akt的失活和通过ERK 1的活化在HSF-1的丝氨酸307上的磷酸化。通过免疫定位、免疫印迹和qPCR实验确定HSF-1和HSP 90和70的定位和表达。采用大鼠角膜微囊实验和荷瘤小鼠体内实验研究了TCCP的抗血管生成作用。因此，所有结果证实了使用TCCP作为癌症治疗的替代方法来灭活HSF-1背后的逻辑。
Heat shock proteins (HSPs), molecular chaperones, are crucial for the cancer cells to facilitate proper functioning of various oncoproteins involved in cell survival, proliferation, migration, and tumor angiogenesis. Tumor cells are said to be "addicted" to HSPs. HSPs are overexpressed in many cancers due to upregulation of transcription factor Heat-shock factor 1 (HSF-1), the multifaceted master regulator of heat shock response. Therefore, pharmacological targeting of HSPs via HSF-1 is an effective strategy to treat malignant cancers like triple negative breast cancer. In the current study, we evaluated the efficacy of a pyrrole derivative [bis(2-ethylhexyl)1H-pyrrole-3,4-dicarboxylate], TCCP, purified from leaves of Tinospora cordifolia for its ability to suppress heat shock response and angiogenesis using MDA-MB-231 cells and the murine mammary carcinoma: Ehrlich ascites tumor model. HSP90 was downregulated by TCCP by inactivation of HSF-1 resulting in inhibition of tumor cell proliferation, VEGF-induced cell migration, and concomitant decrease in tumor burden and neo-angiogenesis in vivo. The mechanism of suppression of HSPs involves inactivation of PI3K/Akt and phosphorylation on serine 307 of HSF-1 by the activation of ERK1. HSF-1 and HSP90 and 70 localization and expression were ascertained by immunolocalization, immunoblotting, and qPCR experiments. The anti-angiogenic effect of TCCP was studied in vivo in tumor-bearing mice and ex vivo using rat corneal micro-pocket assay. All the results thus corroborate the logic behind inactivating HSF-1 using TCCP as an alternative approach for cancer therapy.