1.Warburg的起源

1921年德国生化学家Otto Warburg发现癌细胞的糖酵解异常活跃,即使在氧气充足的情况下仍优先通过糖酵解代谢葡萄糖生成ATP。肿瘤细胞的这种特殊生化表型,称为Warburg效应,或有氧糖酵解。Otto Warburg也因为发现细胞呼吸氧化转移酶而获得了 1931年诺贝尔生理学或医学奖。而癌症代谢生物学近年来成为了生物学领域的又一热点。

 

氧化磷酸化、糖酵解和有氧糖酵解(Warburg效应)的区别

 

2.Warburg的作用机理

研究表明,EGFR激活后可诱导丙酮酸激酶M2 (PKM2)的磷酸化,而不是PKM1,发生核易位。在细胞核中结合并激活β-catenin;磷酸化组蛋白H3,并发生乙酰化;导致糖酵解基因表达上调,提高葡萄糖摄取和乳酸生成。在肿瘤细胞增殖、细胞周期进展和脑肿瘤发生中起重要作用。

 

PKM2通过H3磷酸化调控基因表达

 

缺氧、EGFR激活、K-Ras G12VB-Raf V600E基因表达会诱导磷酸甘油酸酯激酶1(PGK1)线粒体易位,这是由Erk依赖的PGK1磷酸化和随后的PIN1介导的顺反异构化介导的。PGK1磷酸化激活丙酮酸脱氢酶激酶1(PDHK1),抑制丙酮酸脱氢酶(PDH)复合物,抑制线粒体丙酮酸代谢,从而促进Warburg效应。

此外,HIF-1αp53肿瘤抑制因子、ROS PI3K/Akt等相关信号分子和信号通路都参与到warburg的进程中。

糖酵解产生的ATP可以支持原发肿瘤的生长。TCA循环也重新成为一个关键的合成代谢中心,支持肿瘤小鼠模型和癌症患者的肿瘤生长;即ETC相关的TCA循环功能完好无损,但通过氧化磷酸化破坏了与 ETC 相关的ATP生成。因此,我们认识到糖酵解和TCA循环都通过代谢产物的生物合成支持肿瘤生长。

通路相关抗体:

序号 名称
1 PKM2 Ab AF5234
2 P-PKM2 (Tyr105) Ab DF7771
3 P-PKM2 (Ser37) Ab AF7231
4 P-PKM2 (Tyr148) Ab AF7230
5 P-PKM2 (Tyr83) Ab AF7228
6 P-PKM2 (Tyr370) Ab AF7229
7 P-PKM2 (Thr45) Ab AF3833
8 EGF Ab DF2225
9 EGFR Ab AF6043
10 P-EGFR (Ser1070) Ab AF3044
11 P-EGFR (Tyr1048)[Tyr1172] Ab AF3047
12 P-EGFR (Tyr1173)[Tyr1197] Ab AF3048
13 P-EGFR (Thr669)[Tyr693] Ab AF3042
14 P-EGFR (Tyr1086)[Tyr1110] Ab AF3046
15 P-EGFR (Ser1026) Ab AF3051
16 P-EGFR (Thr678) Ab AF3041
17 P-EGFR (Tyr1068)[Tyr1092] Ab AF3045
18 P-EGFR (Tyr992)[Tyr1016] Ab AF3043
19 P-EGFR (Tyr845)[Tyr869] Ab AF3049
20 P-EGFR (Ser695) Ab AF3050
21 P-EGFR (Ser1071) Ab AF3052
22 P-EGFR (Tyr998) Ab AF8110
23 ERK1/2 Ab AF0155
24 p44/42 MAPK (Erk1/2) Mouse monoclonal Ab BF8004
25 P-ERK1/2 (Thr202/Tyr204) Ab AF1015
26 P-ERK1/2 (Tyr204) Ab AF1014
27 P-ERK1/2 (Thr202+Tyr204/Thr185+Tyr187) Ab AF8208
28 P-ERK1/2 (Thr202) Ab AF3240
29 P-ERK1/2 (Tyr205/Tyr222) Ab AF3975
30 P-ERK1/2 (Thr177/Thr160) Ab AF3687
31 ERK2 Ab DF6032
32 Pin1 Ab DF6830
33 P-Pin1 (Ser16) Ab AF3430
34 KPNA1 Ab DF6587
35 beta Catenin Ab AF6266
36 P-beta Catenin (Ser33/Ser37/Thr41) Ab DF2989
37 P-beta Catenin (Ser37) Ab AF3266
38 P-beta Catenin (Thr41/Ser45) Ab AF3268
39 P-beta Catenin (Ser552) Ab AF8340
40 P-beta Catenin (Ser33) Ab AF3267
41 P-beta Catenin (Tyr489) Ab AF3269
42 P-beta Catenin (Ser675) Ab AF8102
43 P-beta Catenin (Tyr142) Ab AF8101
44 P-beta Catenin (Tyr670) Ab AF3679
45 P-beta Catenin (Tyr654) Ab AF3797
46 P-beta Catenin (Tyr333) Ab AF3681
47 c-Myc Ab AF0358
48 P-c-Myc (Ser62) Ab AF3054
49 P-c-Myc (Thr58) Ab AF3055
50 P-c-Myc (Ser293) Ab AF7174
51 GLUT1 Ab AF0173
52 P-GLUT1 (Ser490) Ab AF3731
53 LDHA Ab DF6280
54 P-LDHA (Tyr10) Ab AF7172
55 P-LDHA (Tyr239) Ab AF7173
56 Src Ab AF6161
57 P-Src (Tyr419) Ab AF3162
58 P-Src (Tyr527)[Tyr530] Ab AF3161
59 P-Src (Ser75) Ab AF3163
60 Cyclin D1 Ab AF0931
61 P-Cyclin D1 (Ser90) Ab AF3234
62 P-Cyclin D1 (Thr286) Ab AF0932
63 P-Cyclin D1 (Thr288) Ab AF8267
64 HDAC3 Ab AF0733
65 P-HDAC3 (Ser424) Ab AF3016
66 Histone H3 Ab AF0863
67 P-Histone H3 (Ser11) Ab AF3358
68 Acetyl-Histone H3 (Lys9/14/18/23/27) Ab AF4365
69 P-Histone H3 (Thr12) Ab AF7336
70 Acetyl-Histone H3 (Lys18) Ab AF1023
71 Acetyl-Histone H3 (Lys23) Ab AF1019
72 P-Histone H3 (Thr81) Ab AF7337
73 Acetyl-Histone H3 (Lys122) Ab AF4362
74 Acetyl-Histone H3 (Lys14) Ab AF4352
75 PGK1 Ab DF6722
76 P-PGK1 (Tyr324) Ab AF8608
77 PDHK1 Ab DF4365
78 P-PDHK1 (Tyr243) Ab AF3586
79 HAT Ab AF0269
80 HIF1A Ab AF1009
81 PI3K p85 alpha Ab AF6241
82 PI3K p85/p55 Ab AF6242
83 P-PI3K p85 (Tyr458)[Tyr467]/p55 (Tyr199) Ab AF3242
84 P-PI3K p85 alpha (Tyr607) Ab AF3241
85 P-PI3K p85 alpha (Tyr508) Ab AF4372
86 P-PI3K p85 alpha (Tyr452) Ab AF4371
87 P-PI3K p85 alpha (Tyr580) Ab AF4370
88 pan-AKT1/2/3 Ab AF6261
89 AKT1 Ab AF0836
90 P-pan-AKT1/2/3 (Ser473) Ab AF0016
91 P-pan-AKT1/2/3 (Thr308) Ab AF3262
92 AKT2 Ab AF6264
93 P-AKT2 (Ser474) Ab AF3264
94 P-AKT1 (Ser124) Ab AF3260
95 P-AKT1 (Ser129) Ab AF3261
96 P-AKT1 (Thr450) Ab AF3259
97 P-AKT1 (Ser473+Tyr474) Ab AF8357
98 P-pan-AKT1/2/3 (Tyr315/Tyr316/Tyr312) Ab AF1022
99 P-AKT1 (Tyr326) Ab AF3961
100 R-Ras Ab DF10319
101 P-R-Ras (Tyr66) Ab AF8509
102 C-RAF Ab AF6065
103 P-C-RAF (Ser338) Ab AF3065
104 P-C-RAF (Ser259) Ab AF3064
105 P-C-RAF (Ser301) Ab AF0047
106 P-C-RAF (Ser621) Ab AF3062
107 P-C-RAF (Ser296) Ab AF3063
108 PDK1 Ab BF0312
109 mTOR Ab AF6308
110 P-mTOR (Ser2448) Ab AF3308
111 P-mTOR (Thr2446) Ab AF3310
112 P-mTOR (Ser2481) Ab AF3309
113 P-mTOR (Ser2454) Ab AF7303
114 NF-kB p65 Ab AF5006
115 P-NF-kB p65 (Ser536) Ab AF2006
116 P-NF-kB p65 (Ser276) Ab AF3387
117 P-NF kappaB p105/p50 (Ser337) Ab AF3219
118 P-NF-kB p65 (Ser311) Ab AF3389
119 P-NF-kB p65 (Ser281) Ab AF3393
120 P-NF-kB p65 (Thr435) Ab AF3392
121 p53 Ab AF0879
122 P-p53 (Ser15) Ab AF3075
123 P-p53 (Ser20) Ab AF3073
124 P-p53 (Ser366) Ab AF3078
125 P-p53 (Ser392) Ab AF3074
126 Acetyl-P53 (Lys382) Ab AF3744
127 Acetyl-p53 (Lys319) Ab AF1024
128 Acetyl-p53 (Lys373) Ab AF4363
129 Glut 4 Ab AF5386

【参考文献】 

[1] Yang W, Zheng Y, Xia Y, et al. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect [J]. Nat Cell Biol, 2012, 14(12): 1295-304.

[2] Yang W, Xia Y, Ji H, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation [J]. Nature, 2011, 480(7375): 118-22.

[3] Yang W, Xia Y, Hawke D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis [J]. Cell, 2012, 150(4): 685-96.

[4] Martinez-Reyes I, Chandel N S. Cancer metabolism: looking forward [J]. Nat Rev Cancer, 2021, 21(10): 669-80.

[5] Li X, Jiang Y, Meisenhelder J, et al. Mitochondria-Translocated PGK1 Functions as a Protein Kinase to Coordinate Glycolysis and the TCA Cycle in Tumorigenesis [J]. Mol Cell, 2016, 61(5): 705-19.

[6] Donohoe D R, Collins L B, Wali A, et al. The Warburg effect dictates the mechanism of butyrate-mediated histone acetylation and cell proliferation [J]. Mol Cell, 2012, 48(4): 612-26.

[7] Damaghi M, West J, Robertson-Tessi M, et al. The harsh microenvironment in early breast cancer selects for a Warburg phenotype [J]. Proc Natl Acad Sci U S A, 2021, 118(3).

 


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