N6-Isopentenyladenosine Impairs Mitochondrial Metabolism through Inhibition of EGFR Translocation on Mitochondria in Glioblastoma Cells.
N6-Isopentenyladenosine Impairs Mitochondrial Metabolism through Inhibition of EGFR Translocation on Mitochondria in Glioblastoma Cells.
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胶质母细胞瘤是侵袭性和不可治愈的脑肿瘤，对治疗有抗性。N6-异戊烯基腺苷（i6 A或iPA）是一种天然衍生的分子，已对其抗神经胶质瘤作用进行了研究。我们发现，iPA治疗诱导细胞代谢的改变，这是由于抑制EGFR在线粒体上的易位和激活细胞死亡后，EGFR A上调。我们的研究结果表明，诱导功能障碍的线粒体通过iPA可能是一个有前途的治疗途径，在胶质母细胞瘤的治疗。多形性胶质母细胞瘤（GBM）是最具侵袭性的恶性脑肿瘤，并且对细胞毒性疗法不敏感。表皮生长因子受体（EGFR）的扩增和外显子2至7的缺失（其产生EGFR变体III（vIII））是GBM的最常见的分子改变，其有助于疾病的侵袭性。最近，已经表明EGFR/EGFRvIII靶向抑制剂通过引起这些受体的线粒体积累来增强线粒体易位，促进肿瘤耐药性;此外，它们通过隔离GBM A来负性调节内源性GBM介导的凋亡，导致GBM细胞中的凋亡反应受损。N6-异戊烯基腺苷（i6 A或iPA）是一种由腺苷连接至衍生自甲羟戊酸途径的异戊烯基组成的细胞分裂素，其通过在体外和体内诱导细胞死亡而对许多肿瘤细胞（包括GBM细胞）具有抗增殖作用。在这里，我们观察到iPA通过阻止EGFR/EGFRvIII易位到线粒体并通过促进线粒体活性的变化允许EkA与它们相互作用来抑制GBM细胞中的线粒体呼吸，从而在细胞死亡中发挥关键作用。我们的研究结果清楚地表明，iPA干扰线粒体生物能量的能力，为治疗GBM的有效策略提供了理论基础。
Glioblastomas are aggressive and incurable brain tumors, being resistant to therapy. N6-isopentenyladenosine (i6A or iPA) is a naturally derived molecule that has been studied for its anti-glioma effects. We found that iPA treatment induces an alteration of cellular metabolism due to inhibition of EGFR translocation on mitochondria and activation of cell death following PUMA upregulation. Our findings suggest that inducing dysfunctional mitochondria through iPA might be a promising therapeutic avenue in the treatment of glioblastoma. Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and is poorly susceptible to cytotoxic therapies. Amplification of the epidermal growth factor receptor (EGFR) and deletion of exons 2 to 7, which generates EGFR variant III (vIII), are the most common molecular alterations of GBMs that contribute to the aggressiveness of the disease. Recently, it has been shown that EGFR/EGFRvIII-targeted inhibitors enhance mitochondrial translocation by causing mitochondrial accumulation of these receptors, promoting the tumor drug resistance; moreover, they negatively modulate intrinsic mitochondria-mediated apoptosis by sequestering PUMA, leading to impaired apoptotic response in GBM cells. N6-isopentenyladenosine (i6A or iPA), a cytokinin consisting of an adenosine linked to an isopentenyl group deriving from the mevalonate pathway, has antiproliferative effects on numerous tumor cells, including GBM cells, by inducing cell death in vitro and in vivo. Here, we observed that iPA inhibits the mitochondrial respiration in GBM cells by preventing the translocation of EGFR/EGFRvIII to the mitochondria and allowing PUMA to interact with them by promoting changes in mitochondrial activity, thus playing a critical role in cell death. Our findings clearly demonstrate that iPA interferes with mitochondrial bioenergetic capacity, providing a rationale for an effective strategy for treating GBM.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
--
作者：
Ambroise G;Portier A;Roders N;Arnoult D;Vazquez A
通讯作者：
Vazquez A
影响因子：
4.7
作者：
Navarra, Giovanna;Pagano, Cristina;Bifulco, Maurizio
通讯作者：
Bifulco, Maurizio
影响因子：
5.3
作者：
Boerner, JL;Demory, ML;Parsons, SJ
通讯作者：
Parsons, SJ
影响因子：
64.5
作者：
Ceccarelli M;Barthel FP;Malta TM;Sabedot TS;Salama SR;Murray BA;Morozova O;Newton Y;Radenbaugh A;Pagnotta SM;Anjum S;Wang J;Manyam G;Zoppoli P;Ling S;Rao AA;Grifford M;Cherniack AD;Zhang H;Poisson L;Carlotti CG Jr;Tirapelli DP;Rao A;Mikkelsen T;Lau CC;Yung WK;Rabadan R;Huse J;Brat DJ;Lehman NL;Barnholtz-Sloan JS;Zheng S;Hess K;Rao G;Meyerson M;Beroukhim R;Cooper L;Akbani R;Wrensch M;Haussler D;Aldape KD;Laird PW;Gutmann DH;TCGA Research Network;Noushmehr H;Iavarone A;Verhaak RG
通讯作者：
Verhaak RG