Apoptosis in Cancer Cells Is Induced by Alternative Splicing of hnRNPA2/B1 Through Splicing of Bcl-x, a Mechanism that Can Be Stimulated by an Extract of the South African Medicinal Plant, Cotyledon orbiculata.
Apoptosis in Cancer Cells Is Induced by Alternative Splicing of hnRNPA2/B1 Through Splicing of Bcl-x, a Mechanism that Can Be Stimulated by an Extract of the South African Medicinal Plant, Cotyledon orbiculata.
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DOI：
10.3389/fonc.2020.547392
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发表时间：
2020
影响因子：
4.7
通讯作者：
Dlamini Z
中科院分区：
文献类型：
--
作者：
Makhafola TJ;Mbele M;Yacqub-Usman K;Hendren A;Haigh DB;Blackley Z;Meyer M;Mongan NP;Bates DO;Dlamini Z
选择性剪接在癌症中是不受控制的，而选择性剪接的产物可以与癌症的特征相联系。靶向选择性剪接可以提供新的有效的癌症治疗方法。我们研究了南非药用植物圆形子叶（Cotyledon orbiculata）粗提物对结肠癌（HCT116）和食管癌（OE33和KYSE70）细胞存活的影响。使用RNASeq，我们发现提取物干扰mRNA调控途径。该提取物使hnRNPA2B1从hnRNPB1剪接到hnRNPA2亚型，导致BCL2L1基因从Bcl-xL切换到Bcl-xS，从而激活caspase-3切割和细胞凋亡。已知的抗癌剪接调剂pladienolide b也能诱导类似的剪接效应。用siRNA敲低hnRNPB1可导致细胞活力下降和caspase-3切割增加，过表达hnRNPB1可阻止环草提取物对细胞凋亡和细胞存活的影响。圆果提取物对hnRNPA2/B1剪接开关的影响增加了hnRNPA2B1与Bcl-xl/s、BCL2、MDM2、cMYC、CD44、CDK6和cJUN mRNA的结合。这些发现表明HCT116、OE33和KYSE癌细胞的凋亡是由hnRNPA2B1和BCL2L1的开关剪接控制的，为hnRNPB1调节细胞凋亡提供了证据。抑制这种剪接可能对结肠癌和食管癌具有治疗潜力。在结肠癌中靶向hnRNPA2B1剪接调控BCL2L1剪接诱导细胞凋亡。这种方法可能是一种有效的治疗策略，可以诱导细胞凋亡，抑制癌细胞增殖和肿瘤进展。在这里，我们发现南非药用植物圆形子叶提取物对癌细胞具有抗增殖作用，其机制是通过hnRNPA2B1和BCL2L1的选择性剪接诱导细胞凋亡。
Alternative splicing is deregulated in cancer and alternatively spliced products can be linked to cancer hallmarks. Targeting alternative splicing could offer novel effective cancer treatments. We investigated the effects of the crude extract of a South African medicinal plant, Cotyledon orbiculata, on cell survival of colon (HCT116) and esophageal (OE33 and KYSE70) cancer cell lines. Using RNASeq, we discovered that the extract interfered with mRNA regulatory pathways. The extract caused hnRNPA2B1 to splice from the hnRNPB1 to the hnRNPA2 isoform, resulting in a switch in the BCL2L1 gene from Bcl-xL to Bcl-xS causing activation of caspase-3-cleavage and apoptosis. Similar splicing effects were induced by the known anti-cancer splicing modulator pladienolide B. Knockdown of hnRNPB1 using siRNA resulted in decreased cell viability and increased caspase-3-cleavage, and over-expression of hnRNPB1 prevented the effect of C. orbiculata extract on apoptosis and cell survival. The effect of the hnRNPA2/B1 splicing switch by the C. orbiculata extract increased hnRNPA2B1 binding to Bcl-xl/s, BCL2, MDM2, cMYC, CD44, CDK6, and cJUN mRNA. These findings suggest that apoptosis in HCT116, OE33, and KYSE cancer cells is controlled by switched splicing of hnRNPA2B1 and BCL2L1, providing evidence that hnRNPB1 regulates apoptosis. Inhibiting this splicing could have therapeutic potential for colon and esophageal cancers. Targeting hnRNPA2B1 splicing in colon cancer regulates splicing of BCL2L1 to induce apoptosis. This approach could be a useful therapeutic strategy to induce apoptosis and restrain cancer cell proliferation and tumor progression. Here, we found that the extract of Cotyledon orbiculata, a South African medicinal plant, had an anti-proliferative effect in cancer cells, mediated by apoptosis induced by alternative splicing of hnRNPA2B1 and BCL2L1.
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影响因子：
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作者：
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影响因子：
168.9
作者：
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作者：
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影响因子：
15.9
作者：
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通讯作者：
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影响因子：
14.9
作者：
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