既往研究發(fā)現(xiàn)實(shí)驗藥物AMPI-109能夠有力殺滅三陰性乳腺癌細(xì)胞，但是培養(yǎng)皿中再有力的證據(jù)也不足以推動藥物進(jìn)入人體臨床試驗，即使是對三陰性乳腺癌這種致死率非常高并且目前很大程度上仍無靶向療法選擇的疾病。
2016年8月15日，英國《自然》旗下《腫瘤發(fā)生》在線發(fā)表美國科羅拉多大學(xué)的研究報告，發(fā)現(xiàn)AMPI-109通過反轉(zhuǎn)肝再生磷酸酶3（PRL-3）的開關(guān)而發(fā)揮作用，抑制這種分子的活性可使三陰性乳腺癌細(xì)胞進(jìn)入休眠或衰老，隨后導(dǎo)致細(xì)胞死亡。
已知細(xì)胞內(nèi)的腫瘤壞死因子受體1（TNF-R1）信號通路，既可以幫助細(xì)胞存活，也可以導(dǎo)致細(xì)胞死亡。但是，導(dǎo)致該通路促進(jìn)存活或促進(jìn)死亡的信號調(diào)節(jié)卻知之甚少，特別是在癌細(xì)胞中。該研究在三陰性乳腺癌細(xì)胞中觀察到PRL-3可能是上述過程的一個調(diào)節(jié)因子。當(dāng)該基因被激活可使細(xì)胞存活，而當(dāng)其失活可使細(xì)胞衰老并最終死亡。
在環(huán)境較好的時候，PRL-3能夠啟動某些基因的表達(dá)，招引免疫系統(tǒng)的某些成分促進(jìn)癌癥生長，而當(dāng)環(huán)境比較惡劣的時候，癌細(xì)胞就會進(jìn)入休眠。該研究利用基因技術(shù)將三陰性乳腺癌PRL-3表達(dá)降低，同時用藥物AMPI-109通過阻斷PRL-3發(fā)揮類似作用，使細(xì)胞發(fā)生衰老和凋亡，發(fā)現(xiàn)AMPI-109的作用效果與之非常類似，表明AMPI-109能夠使細(xì)胞進(jìn)入衰老，并且之后會讓癌細(xì)胞度過該階段進(jìn)入凋亡程序。
如今，免疫療法正逐漸成為多種癌癥一線治療選擇。簡而言之，這種策略能夠教會免疫系統(tǒng)識別并攻擊腫瘤組織，但是某些癌癥比較善于躲避免疫系統(tǒng)的攻擊，因此許多免疫療法都只能將癌癥的發(fā)展維持在比較低的水平而無法完全清除。事實(shí)上某些免疫療法也將癌癥作為一種慢性疾病進(jìn)行治療，通過持續(xù)治療無限期地遏制癌癥發(fā)展。
該研究提出，通過類似AMPI-109的藥物抑制PRL-3活性，可以向免疫系統(tǒng)發(fā)送信號對腫瘤進(jìn)行定位，還可以增加腫瘤對免疫治療的敏感性，從本質(zhì)上提高腫瘤的免疫治療效果。如果進(jìn)一步研究結(jié)果仍然明確支持該研究結(jié)論，AMPI-109將有可能成為借助免疫療法靶向治療三陰性乳腺癌的有力工具。
Oncogenesis. 2016 Aug 15;5(8):e255.
Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth.
Gari HH, DeGala GD, Lucia MS, Lambert JR.
University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Stimulating tumor cell senescence and apoptosis are proven methods for therapeutically combating cancer. However, senescence and apoptosis are conventionally viewed as parallel, not sequential, processes. We have discovered that the metastasis-promoting phosphatase, PRL-3, is transcriptionally regulated by the NF-κB pathway in triple-negative breast cancer (TNBC) cells, and that PRL-3 knockdown elicits an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop that results in TNBC cell senescence followed by apoptosis. Knockdown of PRL-3 leads to rapid G1 cell cycle arrest and induction of a strong TNFα cytokine response that promotes a period of cellular senescence through TNF-R1-mediated activation of NF-κB. Senescent PRL-3 knockdown cells subsequently underwent apoptosis as a result of increased TNF-R1 signaling through the TNFα-associated extrinsic death pathway, shunting signaling away from the NF-κB cascade. These data suggest that TNF-R1 signaling dynamically re-programs after PRL-3 knockdown, from sustaining cell senescence through NF-κB to promoting apoptosis through TNF-R1 internalization and caspase-8 activation. The molecular mechanisms that determine the survival-death balance of TNF-R1 signaling are poorly understood, despite the fact that TNF-R1 has been extensively studied. Our results describe PRL-3 knockdown as a novel survival-death balance modifier of the TNF-R1 pathway, and show that senescent TNBC tumor cells can be sensitized to undergo apoptosis in a sequential manner.
PMID: 27526109
DOI: 10.1038/oncsis.2016.50
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