Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling.
Beta 2 adrenergic receptor and mu opioid receptor interact to potentiate the aggressiveness of human breast cancer cell by activating the glycogen synthase kinase 3 signaling.
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β 2肾上腺素能受体和μ阿片受体相互作用通过激活糖原合成酶激酶3信号增强人乳腺癌细胞的侵袭性。
DOI：
10.1186/s13058-022-01526-y
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发表时间：
2022-05-14
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阿片受体和β -肾上腺素能受体最近被证明通过形成受体异二聚体进行串扰，以控制乳腺癌细胞的生长和增殖。然而，潜在的细胞信号传导机制仍不清楚。为了确定这两个系统的相互作用在乳腺癌中的作用，我们利用三阴性乳腺癌细胞系MDA-MB-231和MDA-MB-468， CRISPR或化学抑制或激活β -肾上腺素能受体（B2AR）和mu-阿片受体（MOR）基因，以及PCR阵列技术，研究了侵袭性肿瘤表型和信号级联反应。我们在这里表明，在三阴性乳腺癌细胞中，通过遗传和药理学工具降低B2AR和MOR的表达导致三阴性乳腺癌细胞在体外和动物异种移植中具有较低的侵袭性表型。基因组分析表明糖原合成酶激酶3 （GSK3）途径可能是参与B2AR和MOR串扰的候选信使系统。GSK3在MDA-MB-231和MDA-MB-468细胞中的失活诱导了与B2AR和/或MOR抑制相似的表型变化，而wortmannin激活GSK3逆转了B2AR和/或MOR敲低对这些细胞的影响。GSK3失活还可以阻止B2AR激动剂去甲肾上腺素或MOR激动剂DAMGO影响MDA-MB-231和MDA-MB-468细胞的增殖。这些数据证实了B2AR和MOR相互作用在控制乳腺癌细胞生长中的作用，并确定了GSK3信号系统在调解这两种受体的串扰中的可能作用。筛选靶向B2AR和MOR相互作用和/或GSK3系统的配体可能有助于发现预防三阴性乳腺癌细胞生长和转移的新药。在线版本包含补充材料，可在10.1186/s13058-022-01526-y获得。
Opioid and beta-adrenergic receptors are recently shown to cross talk via formation of receptor heterodimers to control the growth and proliferation of breast cancer cells. However, the underlying cell signaling mechanism remained unclear. To determine the effect of the interaction of the two systems in breast cancer, we employed triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468, CRISPR or chemical inhibition or activation of beta-adrenergic receptors (B2AR) and mu-opioid receptors (MOR) gene, and PCR array technology and studied aggressive tumor phenotype and signaling cascades. We show here that in triple-negative breast cancer cells, the reduction in expression B2AR and MOR by genetic and pharmacological tools leads to a less aggressive phenotype of triple-negative breast cancer cells in vitro and in animal xenografts. Genomic analysis indicates the glycogen synthase kinase 3 (GSK3) pathway as a possible candidate messenger system involved in B2AR and MOR cross talk. GSK3 inactivation in MDA-MB-231 and MDA-MB-468 cells induced similar phenotypic changes as the inhibition of B2AR and/or MOR, while a GSK3 activation by wortmannin reversed the effects of B2AR and/or MOR knockdown on these cells. GSK3 inactivation also prevents B2AR agonist norepinephrine or MOR agonist DAMGO from affecting MDA-MB-231 and MDA-MB-468 cell proliferation. These data confirm a role of B2AR and MOR interaction in the control of breast cancer cell growth and identify a possible role of the GSK3 signaling system in mediation of these two receptors’ cross talk. Screening for ligands targeting B2AR and MOR interaction and/or the GSK3 system may help to identify novel drugs for the prevention of triple-negative breast cancer cell growth and metastasis. The online version contains supplementary material available at 10.1186/s13058-022-01526-y.
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影响因子：
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