FOXO3对PERK表达的调节：耐药癌细胞的脆弱性。,Oncogene

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FOXO3对PERK表达的调节：耐药癌细胞的脆弱性。
Oncogene ( IF 6.9 ) Pub Date : 2019-07-16 , DOI: 10.1038/s41388-019-0890-7
Glowi Alasiri ₁ , Yannasittha Jiramongkol ₁ , Stefania Zona ₁ , Lavender Y-N Fan ₁ , Zimam Mahmud ₁ , Gyungyub Gong ₂ , Hee Jin Lee ₂ , Eric W-F Lam ₁

Affiliation

有效癌症治疗的主要障碍是耐药性的发展。肿瘤抑制转录因子FOXO3促进细胞周期停滞，衰老和细胞死亡，并介导癌症治疗剂的细胞毒性和细胞抑制功能。因此，FOXO3通常被下调为癌症特别是化疗药物耐药细胞中的适应性反应。一致地，我们发现与亲代MCF-7乳腺癌细胞相比，耐药性MCF-7-EpiR和MCF-7-TaxR中的FOXO3表达减弱。使用ChIP，短干扰RNA（siRNA）敲低和过表达测定以及Foxo1 / 3/4-/-MEF，我们将内质网（ER）应激防御调节剂PERK（eIF2AK3）建立为直接下游转录靶标的FOXO3。同意乳腺癌患者样品中FOXO3和PERK在蛋白质和RNA水平的表达也呈正相关。我们发现PERK表达下调，但其活性在耐药细胞中组成性升高。考虑到这一点，我们利用了低水平的FOXO3和PERK表达以及在耐药性乳腺癌细胞中具有较高的PERK活性的这种适应性反应，并表明这些耐药性细胞对PERK的抑制作用特别敏感。为了支持这一发现，我们表明异位表达FOXO3可以降低耐药细胞对PERK抑制剂GSK2606414的敏感性，而表达较低水平PERK的Foxo1 / 3/4-/-MEF对PERK抑制的敏感性更高。野生型MEF。PERK抑制剂的滴定和时程实验表明，与亲本MCF-7细胞相比，表达较低的PERK和较高的PERK活性水平的耐药细胞对PERK抑制剂浓度的增加更敏感。因此，我们目前的工作揭示了PERK的化疗耐药性癌细胞的脆弱性，并建议PERK作为潜在的癌症治疗靶标，特别是在耐药性癌症的情况下。

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Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells.

The major impediment to effective cancer therapy has been the development of drug resistance. The tumour suppressive transcription factor FOXO3 promotes cell cycle arrest, senescence and cell death, and mediates the cytotoxic and cytostatic functions of cancer therapeutics. In consequence, FOXO3 is often downregulated as an adaptive response in cancer and particularly in chemotherapeutic drug-resistant cells. Consistently, we find that FOXO3 expression is attenuated in the drug-resistant MCF-7-EpiR and MCF-7-TaxR compared to the parental MCF-7 breast cancer cells. Using ChIP, short-interfering RNA (siRNA) knockdown, and overexpression assays as well as Foxo1/3/4-/- MEFs, we establish the endoplasmic reticulum (ER)-stress defence modulator PERK (eIF2AK3) as a direct downstream transcriptional target of FOXO3. In agreement, there is also a positive correlation between FOXO3 and PERK expression at the protein and RNA levels in breast cancer patient samples. We uncover that PERK expression is downregulated but its activity constitutively elevated in the drug-resistant cells. With this in mind, we exploit this adaptive response of low FOXO3 and PERK expression, and high PERK activity in drug-resistant breast cancer cells and show that these drug-resistant cells are specifically sensitive to PERK inhibition. In support of this finding, we show that ectopic overexpression of FOXO3 can reduce the sensitivity of the resistant cells to the PERK inhibitor GSK2606414, while the Foxo1/3/4-/- MEFs expressing lower levels of PERK are more sensitive to PERK inhibition compared to wild-type MEFs. PERK inhibitor-titration and -time course experiments showed that the drug-resistant cells, which express lower expression and higher activity levels of PERK, are more sensitive to the increasing concentrations of PERK inhibitor compared to parental MCF-7 cells. Our present work thus reveals a chemotherapeutic drug-resistant cancer cell vulnerability in PERK and suggests PERK as a potential target for cancer therapy, specifically in the context of drug-resistant cancers.

更新日期：2019-07-17

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