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棉酚通过阻断 Ca3 钙通道诱导结肠癌细胞 G/G 细胞周期停滞。

Blockade of Ca3 calcium channels and induction of G/G cell cycle arrest in colon cancer cells by gossypol.

机构信息

Departamento de Neuropatología Molecular, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.

Université de Tours, Inserm U1327 ISCHEMIA 'Membrane Signalling and Inflammation in Reperfusion Injuries', Tours, France.

出版信息

Br J Pharmacol. 2024 Nov;181(22):4546-4570. doi: 10.1111/bph.16497. Epub 2024 Jul 31.

DOI:10.1111/bph.16497
PMID:39081110
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11613961/
Abstract

BACKGROUND AND PURPOSE

Gastrointestinal tumours overexpress voltage-gated calcium (Ca3) channels (Ca3.1, 3.2 and 3.3). Ca3 channels regulate cell growth and apoptosis colorectal cancer. Gossypol, a polyphenolic aldehyde found in the cotton plant, has anti-tumour properties and inhibits Ca3 currents. A systematic study was performed on gossypol blocking mechanism on Ca3 channels and its potential anticancer effects in colon cancer cells, which express Ca3 isoforms.

EXPERIMENTAL APPROACH

Transcripts for Ca3 proteins were analysed in gastrointestinal cancers using public repositories and in human colorectal cancer cell lines HCT116, SW480 and SW620. The gossypol blocking mechanism on Ca3 channels was investigated by combining heterologous expression systems and patch-clamp experiments. The anti-tumoural properties of gossypol were estimated by cell proliferation, viability and cell cycle assays. Ca dynamics were evaluated with cytosolic and endoplasmic reticulum (ER) Ca indicators.

KEY RESULTS

High levels of Ca3 transcripts correlate with poor prognosis in gastrointestinal cancers. Gossypol blockade of Ca3 isoforms is concentration- and use-dependent interacting with the closed, activated and inactivated conformations of Ca3 channels. Gossypol and Ca3 channels down-regulation inhibit colorectal cancer cell proliferation by arresting cell cycles at the G/G and G/M phases, respectively. Ca3 channels underlie the vectorial Ca uptake by endoplasmic reticulum in colorectal cancer cells.

CONCLUSION AND IMPLICATIONS

Gossypol differentially blocked Ca3 channel and its anticancer activity was correlated with high levels of Ca3.1 and Ca3.2 in colorectal cancer cells. The Ca3 regulates cell proliferation and Ca dynamics in colorectal cancer cells. Understanding this blocking mechanism maybe improve cancer therapies.

摘要

背景与目的

胃肠道肿瘤过度表达电压门控钙（Ca3）通道（Ca3.1、3.2 和 3.3）。Ca3 通道调节细胞生长和结肠直肠癌细胞凋亡。存在于棉花植物中的多酚醛基化合物棉酚具有抗肿瘤特性，并抑制 Ca3 电流。对棉酚阻断 Ca3 通道的机制及其在表达 Ca3 同工型的结肠癌细胞中的潜在抗癌作用进行了系统研究。

实验方法

使用公共数据库分析胃肠道癌症中的 Ca3 蛋白转录本，并在人结肠癌细胞系 HCT116、SW480 和 SW620 中进行分析。通过结合异源表达系统和膜片钳实验研究了棉酚对 Ca3 通道的阻断机制。通过细胞增殖、活力和细胞周期测定评估棉酚的抗肿瘤特性。通过细胞质和内质网（ER）Ca 指示剂评估 Ca 动力学。

主要结果

Ca3 转录物水平与胃肠道癌症的预后不良相关。棉酚对 Ca3 同工型的阻断作用呈浓度和使用依赖性，与 Ca3 通道的关闭、激活和失活构象相互作用。棉酚和 Ca3 通道下调通过分别将细胞周期阻滞在 G/G 和 G/M 期来抑制结肠癌细胞增殖。Ca3 通道是结肠直肠癌细胞内质网向量性 Ca 摄取的基础。

结论和意义

棉酚差异阻断 Ca3 通道，其抗癌活性与结肠癌细胞中 Ca3.1 和 Ca3.2 水平升高相关。Ca3 调节结肠直肠癌细胞的增殖和 Ca 动力学。了解这种阻断机制可能会改善癌症治疗。

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