摘要:膳食脂肪通过改变细胞膜脂质含量影响PI3K/AKT通路来影响胰腺癌的进展

C. Torres, Georgina Mancinelli, Emily Chen, J. Cordoba-Chacon, D. Pins, R. McKinney, Sara Saeed, Karla J. Castellanos, G. Orsi, M. Singhal, S. Grimaldo, Poorna Chandra Rao Yalagala, P. Subbaiah, Cecilia Leal, P. Grippo
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引用次数: 0

摘要

胰腺癌(PC)是少数几种发病率和死亡率持续上升的癌症之一,尽管人们对其病因和危险因素的了解不断增加。在后者中,饮食模式与PC风险显著相关。由于其进展相对缓慢,预防性战略是改善结果的一种简单手段。我们有兴趣了解饮食对PC预防的影响,并在体外(通过PC细胞系)和体内(分别通过EL-KrasG12D和p48Cre/LSL-KrasG12D小鼠模型,分别概括IPMN和panin样病变)研究了多不饱和脂肪酸(PUFAs)在疾病进展中的作用。我们的数据表明,膳食PUFAs被纳入质膜磷脂(PL),影响信号转导,特别是PI3K/AKT信号传导,支持膜靶向治疗的出现。我们评估了补充omega-3 (ω-3)或omega-6 (ω-6) PUFAs的饮食对肿瘤病变发展的影响。本研究支持ω-3降低而ω-6加速与pAKT变化相关的病变外显率、肿瘤形成和增殖。这些结果也在体外重现,以证实当与ω-3富含饮食的主要成分二十二碳六烯酸(DHA)孵育时,PI3K/AKT通路的活性降低。当ω-6富集饮食的主要成分亚油酸(LA)被过量激活时,这种效应被消除了。由于PI3K的活性依赖于其与膜上PIP2的结合,我们下一步的目标是研究PUFAs是否改变了PL的组成。通过使用IF和稳定转染的PC细胞,并使用荧光易位生物传感器监测膜中的PIP2和PIP3脂质,我们发现外源脂肪酸在质膜中以PIP2与PIP3的比例表达的影响。在la处理的Panc-1细胞中观察到膜GFP染色(或PIP3)富集区。DHA处理可阻止PIP3在肿瘤细胞膜中的定位,使GFP信号在细胞质中保持弥漫性。使用PIP2生物传感器,我们试图研究PI3K对PIP2的亲和力,这取决于DHA或LA在PIP2中的掺入。DHA处理降低了PI3K与PIP2的相互作用(不是总PI3K),导致膜中PIP3水平降低,pAKT激活降低。我们的研究结果令人鼓舞,因为这些PUFAs影响Kras的下游靶点AKT,这是Kras难以捉摸的治疗方法和PI3K/AKT通路抑制的毒性作用的合理替代方案。引文格式:Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo。膳食脂肪通过改变细胞膜脂质含量影响PI3K/AKT通路影响胰腺癌进展[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2581。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract 2581: Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway
Pancreatic cancer (PC) is one of the few cancers for which incidence and mortality continue to rise despite increasing knowledge of its etiology and risk factors. Amongst the latter, dietary patterns are significantly associated with PC risk. Due to its relatively slow progression, preventive strategies represent a simple means to improve outcomes. We are interested in understanding the influence of diet on PC prevention and have studied the effects of polyunsaturated fatty acids (PUFAs) in the progression of the disease both in vitro (via PC cell lines) and in vivo (via EL-KrasG12D and p48Cre/LSL-KrasG12D mouse models that recapitulate IPMN- and PanIN-like lesions, respectively). Our data demonstrate that dietary PUFAs are incorporated into plasma membrane phospholipids (PL) affecting signal transduction, particularly PI3K/AKT signaling, supporting the emergence of membrane-targeted therapies. We evaluated the effects of diets supplemented with omega-3 (ω-3) or omega-6 (ω-6) PUFAs on neoplastic lesion development. This work supports that ω-3 reduces while ω-6 accelerates lesion penetrance, tumor formation and proliferation associated with changes in pAKT. These results were also recapitulated in vitro to confirm that reduced activity of the PI3K/AKT pathway when incubated with Docosahexaenoic Acid (DHA), the primary component of the ω-3 enriched diet. This effect was abrogated by over-activation of the pathway when dosed with the main component of the ω-6 enriched diet, Linoleic Acid (LA). Since PI3K depends on its binding to PIP2 in the membrane for its activity, we next aimed to study if PUFAs were altering PL composition. By using IF and stably-transfected PC cells with a fluorescent translocation biosensor to monitor PIP2 and PIP3 lipids in the membrane, we discovered an effect of exogenous fatty acids expressed as a ratio of PIP2 to PIP3 in the plasma membrane. Enriched areas of membrane GFP staining (or PIP3) were observed in LA-treated Panc-1 cells. DHA treatment prevented PIP3 localization in the membrane of tumor cells, keeping the GFP signal diffuse in the cytoplasm. Using the PIP2 biosensor we sought to study the affinity of PI3K for PIP2 depending on the incorporation of DHA or LA in PIP2. DHA treatment reduced PI3K interaction (not total PI3K) with PIP2 resulting in lower levels of PIP3 in the membrane and reduced pAKT activation. Our results are encouraging because these PUFAs impinge on AKT, a downstream target of Kras which serves as a logical alternative to the elusive therapies for Kras and often toxic effects of PI3K/AKT pathway inhibition. Citation Format: Carolina Torres, Georgina Mancinelli, Emily Chen, Jose Cordoba-Chacon, Danielle Pins, Ronald McKinney, Sara Saeed, Karla Castellanos, Giulia Orsi, Megha Singhal, Sam Grimaldo, Poorna Chandra Rao Yalagala, Papasani Subbaiah, Cecilia Leal, Paul Grippo. Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2581.
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