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β受体阻滞剂普萘洛尔抑制缺氧诱导的碳酸酐酶 IX 的表达对结直肠癌细胞增殖和转移潜能的影响。

Impairment of Hypoxia-Induced CA IX by Beta-Blocker Propranolol-Impact on Progression and Metastatic Potential of Colorectal Cancer Cells.

机构信息

Biomedical Research Centre, Department of Tumor Biology, Institute of Virology, Slovak Academy of Sciences Dubravska cesta 9, 84505 Bratislava, Slovakia.

Ruzinov Hospital, University Hospital Bratislava, Ruzinovska 6, 82101 Bratislava, Slovakia.

出版信息

Int J Mol Sci. 2020 Nov 19;21(22):8760. doi: 10.3390/ijms21228760.

DOI:10.3390/ijms21228760
PMID:33228233
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7699498/
Abstract

The coexistence of cancer and other concomitant diseases is very frequent and has substantial implications for treatment decisions and outcomes. Beta-blockers, agents that block the beta-adrenergic receptors, have been related also to cancers. In the model of multicellular spheroids formed by colorectal cancer cells we described a crosstalk between beta-blockade by propranolol and tumour microenvironment. Non-selective beta-blocker propranolol decreased ability of tumour cells to adapt to hypoxia by reducing levels of HIF1α and carbonic anhydrase IX in 3D spheroids. We indicated a double action of propranolol in the tumour microenvironment by inhibiting the stability of HIF1α, thus mediating decrease of CA IX expression and, at the same time, by its possible effect on CA IX activity by decreasing the activity of protein kinase A (PKA). Moreover, the inhibition of β-adrenoreceptors by propranolol enhanced apoptosis, decreased number of mitochondria and lowered the amount of proteins involved in oxidative phosphorylation (V-ATP5A, IV-COX2, III-UQCRC2, II-SDHB, I-NDUFB8). Propranolol reduced metastatic potential, viability and proliferation of colorectal cancer cells cultivated in multicellular spheroids. To choose the right treatment strategy, it is extremely important to know how the treatment of concomitant diseases affects the superior microenvironment that is directly related to the efficiency of anti-cancer therapy.

摘要

癌症与其他并存疾病的共存非常普遍，对治疗决策和结果有重大影响。β受体阻滞剂，即阻断β肾上腺素能受体的药物，也与癌症有关。在由结直肠癌细胞形成的多细胞球体模型中，我们描述了β阻断（由普萘洛尔引起）与肿瘤微环境之间的串扰。非选择性β受体阻滞剂普萘洛尔通过降低 3D 球体中 HIF1α 和碳酸酐酶 IX 的水平，降低肿瘤细胞适应缺氧的能力。我们通过抑制 HIF1α 的稳定性，在肿瘤微环境中指示了普萘洛尔的双重作用，从而介导 CAIX 表达的降低，同时通过降低蛋白激酶 A（PKA）的活性来影响 CAIX 活性。此外，普萘洛尔对β肾上腺素受体的抑制作用增强了细胞凋亡，减少了线粒体的数量，并降低了参与氧化磷酸化的蛋白质的数量（V-ATP5A、IV-COX2、III-UQCRC2、II-SDHB、I-NDUFB8）。普萘洛尔降低了在多细胞球体中培养的结直肠癌细胞的转移潜力、活力和增殖能力。为了选择正确的治疗策略，了解并存疾病的治疗如何影响与抗癌治疗效率直接相关的优越微环境极其重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/872b/7699498/94efc2e603c2/ijms-21-08760-g006.jpg
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