Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol.
Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol.
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DOI：
10.3390/ijms23095269
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发表时间：
2022-05-09
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
Warburg效应通常被认为是几乎所有肿瘤的标志。在前列腺癌（PCa）中，它被证明是由PTEN缺失和Akt过度激活相关的己糖激酶2 （HK2）上调驱动的。δ-生育三烯醇（δ-TT）是一种被广泛研究的抗肿瘤化合物；然而，其在影响PCa糖酵解中的作用尚不清楚。在此，我们证明δ-TT通过特异性降低HK2表达抑制pten缺失的LNCaP和PC3 PCa细胞的葡萄糖摄取和乳酸生成。值得注意的是，这伴随着Akt通路的抑制。此外，该营养品可与降糖药二甲双胍协同诱导PCa细胞死亡，这表明上述代谢表型在δ- tt介导的细胞毒性中起着至关重要的作用。总的来说，这些结果揭示了δ-TT对PCa中糖酵解重编程的新型抑制作用，从而为其抗肿瘤活性的机制及其在联合治疗中的应用提供了新的视角。
The Warburg effect is commonly recognized as a hallmark of nearly all tumors. In prostate cancer (PCa), it has been shown to be driven by PTEN loss- and Akt hyperactivation-associated upregulation of hexokinase 2 (HK2). δ-Tocotrienol (δ-TT) is an extensively studied antitumor compound; however, its role in affecting PCa glycolysis is still unclear. Herein, we demonstrated that δ-TT inhibits glucose uptake and lactate production in PTEN-deficient LNCaP and PC3 PCa cells, by specifically decreasing HK2 expression. Notably, this was accompanied by the inhibition of the Akt pathway. Moreover, the nutraceutical could synergize with the well-known hypoglycemic agent metformin in inducing PCa cell death, highlighting the crucial role of the above metabolic phenotype in δ-TT-mediated cytotoxicity. Collectively, these results unravel novel inhibitory effects of δ-TT on glycolytic reprogramming in PCa, thus providing new perspectives into the mechanisms of its antitumor activity and into its use in combination therapy.
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影响因子：
13.8
作者：
Liberti MV;Locasale JW
通讯作者：
Locasale JW
影响因子：
2.2
作者：
Beretta, Giangiacomo;Gelmini, Fabrizio;Limonta, Patrizia
通讯作者：
Limonta, Patrizia
影响因子：
9.3
作者：
Abdel-Wahab, Ali F.;Mahmoud, Waheed;Al-Harizy, Randa M.
通讯作者：
Al-Harizy, Randa M.
影响因子：
28.4
作者：
Global Burden of Disease Cancer Collaboration;Fitzmaurice C;Allen C;Barber RM;Barregard L;Bhutta ZA;Brenner H;Dicker DJ;Chimed-Orchir O;Dandona R;Dandona L;Fleming T;Forouzanfar MH;Hancock J;Hay RJ;Hunter-Merrill R;Huynh C;Hosgood HD;Johnson CO;Jonas JB;Khubchandani J;Kumar GA;Kutz M;Lan Q;Larson HJ;Liang X;Lim SS;Lopez AD;MacIntyre MF;Marczak L;Marquez N;Mokdad AH;Pinho C;Pourmalek F;Salomon JA;Sanabria JR;Sandar L;Sartorius B;Schwartz SM;Shackelford KA;Shibuya K;Stanaway J;Steiner C;Sun J;Takahashi K;Vollset SE;Vos T;Wagner JA;Wang H;Westerman R;Zeeb H;Zoeckler L;Abd-Allah F;Ahmed MB;Alabed S;Alam NK;Aldhahri SF;Alem G;Alemayohu MA;Ali R;Al-Raddadi R;Amare A;Amoako Y;Artaman A;Asayesh H;Atnafu N;Awasthi A;Saleem HB;Barac A;Bedi N;Bensenor I;Berhane A;Bernabé E;Betsu B;Binagwaho A;Boneya D;Campos-Nonato I;Castañeda-Orjuela C;Catalá-López F;Chiang P;Chibueze C;Chitheer A;Choi JY;Cowie B;Damtew S;das Neves J;Dey S;Dharmaratne S;Dhillon P;Ding E;Driscoll T;Ekwueme D;Endries AY;Farvid M;Farzadfar F;Fernandes J;Fischer F;G/Hiwot TT;Gebru A;Gopalani S;Hailu A;Horino M;Horita N;Husseini A;Huybrechts I;Inoue M;Islami F;Jakovljevic M;James S;Javanbakht M;Jee SH;Kasaeian A;Kedir MS;Khader YS;Khang YH;Kim D;Leigh J;Linn S;Lunevicius R;El Razek HMA;Malekzadeh R;Malta DC;Marcenes W;Markos D;Melaku YA;Meles KG;Mendoza W;Mengiste DT;Meretoja TJ;Miller TR;Mohammad KA;Mohammadi A;Mohammed S;Moradi-Lakeh M;Nagel G;Nand D;Le Nguyen Q;Nolte S;Ogbo FA;Oladimeji KE;Oren E;Pa M;Park EK;Pereira DM;Plass D;Qorbani M;Radfar A;Rafay A;Rahman M;Rana SM;Søreide K;Satpathy M;Sawhney M;Sepanlou SG;Shaikh MA;She J;Shiue I;Shore HR;Shrime MG;So S;Soneji S;Stathopoulou V;Stroumpoulis K;Sufiyan MB;Sykes BL;Tabarés-Seisdedos R;Tadese F;Tedla BA;Tessema GA;Thakur JS;Tran BX;Ukwaja KN;Uzochukwu BSC;Vlassov VV;Weiderpass E;Wubshet Terefe M;Yebyo HG;Yimam HH;Yonemoto N;Younis MZ;Yu C;Zaidi Z;Zaki MES;Zenebe ZM;Murray CJL;Naghavi M
通讯作者：
Naghavi M
影响因子：
3.9
作者：
He, Zhikuan;Dong, Wenxing;Yao, Kunhou;Qin, Changjiang;Duan, Baomin
通讯作者：
Duan, Baomin