Abstract
Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC- 1α/PPARGC1A) is a pivotal transcriptional coactivator involved in the regulation of mitochondrial metabolism, including biogenesis and oxidative metabolism. PGC-1α is finely regulated by AMPactivated protein kinases (AMPKs), the role of which in tumors remains controversial to date. In recent years, a growing amount of research on PGC-1α and tumor metabolism has emphasized its importance in a variety of tumors, including prostate cancer (PCA). Compelling evidence has shown that PGC-1α may play dual roles in promoting and inhibiting tumor development under certain conditions. Therefore, a better understanding of the critical role of PGC-1α in PCA pathogenesis will provide new insights into targeting PGC-1α for the treatment of this disease. In this review, we highlight the procancer and anticancer effects of PGC-1α in PCA and aim to provide a theoretical basis for targeting AMPK/PGC-1α to inhibit the development of PCA. In addition, our recent findings provide a candidate drug target and theoretical basis for targeting PGC-1α to regulate lipid metabolism in PCA.
Keywords: Prostate cancer, peroxisome proliferator-activated receptor gamma coactivator-1 alpha, AMP-activated protein kinases, mitochondrial metabolism, adipocyte thermogenesis, Warburg effect.
Graphical Abstract
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[http://dx.doi.org/10.3322/caac.21338] [PMID: 26808342]
[http://dx.doi.org/10.1038/onc.2013.235] [PMID: 23752196]
[http://dx.doi.org/10.1016/j.ccr.2010.05.026] [PMID: 20579941]
[http://dx.doi.org/10.1056/NEJMoa1911206] [PMID: 31566937]
[http://dx.doi.org/10.1093/annonc/mdx155] [PMID: 28472366]
[http://dx.doi.org/10.1056/NEJMoa1911440] [PMID: 32343890]
[http://dx.doi.org/10.1056/NEJMoa2022485] [PMID: 32955174]
[http://dx.doi.org/10.1016/j.eururo.2020.09.046] [PMID: 33039206]
[http://dx.doi.org/10.1146/annurev-med-051517-011947] [PMID: 30691365]
[http://dx.doi.org/10.1080/21681805.2020.1739139] [PMID: 32266854]
[http://dx.doi.org/10.1016/S0092-8674(00)81410-5] [PMID: 9529258]
[http://dx.doi.org/10.1038/nrc3038] [PMID: 21508971]
[http://dx.doi.org/10.1038/onc.2013.463] [PMID: 24186207]
[http://dx.doi.org/10.1016/j.cmet.2007.10.002] [PMID: 18177721]
[http://dx.doi.org/10.1002/pros.22703] [PMID: 23818177]
[http://dx.doi.org/10.3389/fonc.2017.00131] [PMID: 28674679]
[http://dx.doi.org/10.3389/fonc.2020.01293] [PMID: 32850402]
[http://dx.doi.org/10.1159/000459195] [PMID: 7308179]
[http://dx.doi.org/10.1038/s41585-020-0288-x] [PMID: 32112053]
[http://dx.doi.org/10.1016/j.mito.2005.02.001] [PMID: 16050980]
[http://dx.doi.org/10.1038/s41467-018-03573-6] [PMID: 29563510]
[http://dx.doi.org/10.1002/ijc.31313] [PMID: 29441565]
[http://dx.doi.org/10.1021/acs.analchem.9b04903] [PMID: 31944670]
[http://dx.doi.org/10.1073/pnas.1813956115] [PMID: 30397150]
[http://dx.doi.org/10.1016/j.mam.2012.11.007] [PMID: 23506906]
[http://dx.doi.org/10.1038/emboj.2011.158] [PMID: 21602788]
[http://dx.doi.org/10.1186/s40170-016-0161-9] [PMID: 27980733]
[http://dx.doi.org/10.4161/cbt.12.12.18367] [PMID: 22156800]
[http://dx.doi.org/10.1080/14728222.2017.1265506] [PMID: 27885880]
[http://dx.doi.org/10.1016/j.abb.2016.04.014] [PMID: 27132038]
[http://dx.doi.org/10.1038/nrurol.2016.272] [PMID: 28169991]
[PMID: 30906622]
[http://dx.doi.org/10.3390/cells9102234] [PMID: 33022986]
[http://dx.doi.org/10.1002/ijc.32253] [PMID: 30848477]
[http://dx.doi.org/10.1158/1535-7163.MCT-15-0621] [PMID: 27197257]
[http://dx.doi.org/10.1038/onc.2015.355] [PMID: 26387540]
[http://dx.doi.org/10.1016/j.ccr.2012.11.020] [PMID: 23416000]
[http://dx.doi.org/10.1016/j.ccr.2013.02.003] [PMID: 23477830]
[http://dx.doi.org/10.1038/nature19347] [PMID: 27580028]
[http://dx.doi.org/10.1038/onc.2017.325] [PMID: 28991225]
[http://dx.doi.org/10.1038/nature15726] [PMID: 26466563]
[http://dx.doi.org/10.1186/2049-3002-1-22] [PMID: 24304688]
[http://dx.doi.org/10.1158/0008-5472.CAN-11-2967] [PMID: 22266114]
[http://dx.doi.org/10.1038/ncb3039]
[http://dx.doi.org/10.1038/ncomms12156] [PMID: 27402251]
[http://dx.doi.org/10.1016/j.cmet.2017.09.006] [PMID: 28988825]
[http://dx.doi.org/10.1016/j.cmet.2015.08.015] [PMID: 26365176]
[http://dx.doi.org/10.18632/oncotarget.1963] [PMID: 25051362]
[http://dx.doi.org/10.1016/j.molcel.2011.08.044] [PMID: 22099309]
[http://dx.doi.org/10.1002/cam4.2659] [PMID: 31663688]
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.03.009] [PMID: 30880247]
[http://dx.doi.org/10.3390/ijms19113534] [PMID: 30423971]
[http://dx.doi.org/10.1038/nrm.2017.95] [PMID: 28974774]
[http://dx.doi.org/10.1038/ncb3357] [PMID: 27214280]
[http://dx.doi.org/10.1158/0008-5472.CAN-18-2043] [PMID: 31064849]
[http://dx.doi.org/10.1158/0008-5472.CAN-19-1231] [PMID: 31594836]
[http://dx.doi.org/10.1016/j.cmet.2021.02.007] [PMID: 33657393]
[http://dx.doi.org/10.1210/me.2009-0302] [PMID: 19884383]
[http://dx.doi.org/10.1038/s41388-019-0805-7] [PMID: 30936458]
[http://dx.doi.org/10.1016/j.celrep.2017.09.026] [PMID: 28978464]
[http://dx.doi.org/10.3892/mmr.2020.11121] [PMID: 32377739]
[http://dx.doi.org/10.1158/0008-5472.CAN-18-0585] [PMID: 30242113]
[http://dx.doi.org/10.1016/j.cmet.2012.12.001] [PMID: 23274086]
[http://dx.doi.org/10.1158/2159-8290.CD-17-1215] [PMID: 29572236]
[http://dx.doi.org/10.7150/thno.20356] [PMID: 29290796]
[http://dx.doi.org/10.1158/2159-8290.CD-18-0513] [PMID: 29967075]
[http://dx.doi.org/10.15252/embj.201490784] [PMID: 25712477]
[http://dx.doi.org/10.1002/pros.23106] [PMID: 26440826]
[http://dx.doi.org/10.1096/fj.201701078R] [PMID: 29505302]
[http://dx.doi.org/10.3390/cells9061441] [PMID: 32531951]
[http://dx.doi.org/10.1016/j.devcel.2018.11.033] [PMID: 30595535]
[http://dx.doi.org/10.1038/pcan.2016.19] [PMID: 27324222]
[http://dx.doi.org/10.1517/14728222.2015.1005603] [PMID: 25600663]
[http://dx.doi.org/10.3390/ijms21228540] [PMID: 33198356]
[http://dx.doi.org/10.3390/ijms20071647] [PMID: 30987073]
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0135] [PMID: 24994714]
[http://dx.doi.org/10.1007/s12253-016-0169-z] [PMID: 28083789]
[http://dx.doi.org/10.1634/theoncologist.2013-0111] [PMID: 24258613]
[http://dx.doi.org/10.2337/dc09-1380] [PMID: 19918015]
[http://dx.doi.org/10.1016/j.juro.2018.06.031] [PMID: 29940252]
[http://dx.doi.org/10.1038/s41391-018-0085-2] [PMID: 30651580]
[http://dx.doi.org/10.1093/nar/gkv047] [PMID: 25628363]
[http://dx.doi.org/10.1016/j.cell.2015.07.016] [PMID: 26232224]
[http://dx.doi.org/10.1038/s41556-018-0118-z] [PMID: 29941933]
[http://dx.doi.org/10.12122/j.issn.1673-4254.2019.12.06] [PMID: 31907158]
[http://dx.doi.org/10.1016/j.ebiom.2017.10.009] [PMID: 29066174]
[http://dx.doi.org/10.1016/j.ccell.2019.03.007] [PMID: 31031016]
[http://dx.doi.org/10.1038/s41598-017-17009-6] [PMID: 29192176]
[PMID: 11325816]
[http://dx.doi.org/10.1038/s41388-018-0278-0] [PMID: 29717261]
[http://dx.doi.org/10.1016/j.ccell.2020.06.001] [PMID: 32649885]
[http://dx.doi.org/10.1002/mc.22731] [PMID: 28876465]
[http://dx.doi.org/10.1073/pnas.0705070104] [PMID: 17609368]
[http://dx.doi.org/10.1097/MOL.0b013e328328d0a4] [PMID: 19276888]
[http://dx.doi.org/10.3945/ajcn.110.001917] [PMID: 21289221]
[http://dx.doi.org/10.1038/s41598-020-77055-5] [PMID: 33230156]
[http://dx.doi.org/10.1038/nature11125] [PMID: 22722839]
[http://dx.doi.org/10.1016/j.cell.2015.05.001] [PMID: 26000489]
[http://dx.doi.org/10.1038/ncb3365] [PMID: 27230528]
[http://dx.doi.org/10.1074/jbc.M110.202390] [PMID: 21454513]
[http://dx.doi.org/10.7150/thno.30398] [PMID: 31037127]
[http://dx.doi.org/10.1038/s41420-020-00347-2] [PMID: 33298860]
[http://dx.doi.org/10.1038/onc.2011.37] [PMID: 21358671]
[http://dx.doi.org/10.1016/j.fct.2016.12.020] [PMID: 27993529]
[http://dx.doi.org/10.1111/cpr.12918] [PMID: 33025691]
[http://dx.doi.org/10.1073/pnas.0808801106] [PMID: 19179292]
[http://dx.doi.org/10.1016/j.cmet.2005.05.002] [PMID: 16054090]
[http://dx.doi.org/10.1016/j.cmet.2005.05.003] [PMID: 16054088]
[http://dx.doi.org/10.1016/j.redox.2019.101109] [PMID: 30686776]
[http://dx.doi.org/10.1016/j.cell.2012.01.021] [PMID: 22304911]
[http://dx.doi.org/10.1002/1878-0261.12019] [PMID: 28085224]
[http://dx.doi.org/10.1186/s12943-018-0825-x] [PMID: 29618386]
[http://dx.doi.org/10.1038/s41568-018-0038-z] [PMID: 30002479]
[http://dx.doi.org/10.1016/j.ccell.2019.01.007] [PMID: 30889378]
[http://dx.doi.org/10.1038/nature22964] [PMID: 28658205]
[http://dx.doi.org/10.1038/s41588-017-0037-0] [PMID: 29335543]
[http://dx.doi.org/10.1530/ERC-15-0556] [PMID: 27130044]
[http://dx.doi.org/10.1016/j.eururo.2016.10.011] [PMID: 27771128]
[http://dx.doi.org/10.1056/NEJMcibr1800808] [PMID: 29694822]
[http://dx.doi.org/10.1038/s41588-017-0027-2] [PMID: 29335545]
[http://dx.doi.org/10.1172/jci.insight.87489] [PMID: 28239646]
[http://dx.doi.org/10.1038/ncomms10230] [PMID: 26756352]
[http://dx.doi.org/10.1158/1535-7163.MCT-14-0102] [PMID: 25527635]
[http://dx.doi.org/10.1002/emmm.201302734] [PMID: 24497570]
[http://dx.doi.org/10.1158/0008-5472.CAN-10-2581] [PMID: 21098087]
[http://dx.doi.org/10.3233/CBM-160467] [PMID: 28453464]
[http://dx.doi.org/10.1016/j.cmet.2016.06.006] [PMID: 27411013]
[http://dx.doi.org/10.1016/j.cmet.2021.08.012] [PMID: 34508696]
[http://dx.doi.org/10.1016/S1470-2045(09)70240-2] [PMID: 19796751]
[http://dx.doi.org/10.1002/jcp.26811] [PMID: 30078199]
[http://dx.doi.org/10.1111/obr.13085] [PMID: 32608573]
[http://dx.doi.org/10.1038/s41574-018-0123-0] [PMID: 30464312]
[http://dx.doi.org/10.1038/s41580-019-0110-x] [PMID: 30824861]
[http://dx.doi.org/10.1038/nature09787] [PMID: 21307849]
[http://dx.doi.org/10.1016/j.molcel.2005.03.027] [PMID: 15866171]
[http://dx.doi.org/10.1073/pnas.0308061100] [PMID: 14985505]
[http://dx.doi.org/10.1158/2159-8290.CD-12-0095] [PMID: 22588877]
[http://dx.doi.org/10.1126/scisignal.2004088] [PMID: 23550210]
[http://dx.doi.org/10.1016/j.cell.2015.10.025] [PMID: 26544944]
[http://dx.doi.org/10.1161/01.HYP.0000158946.53289.24] [PMID: 15738346]
[http://dx.doi.org/10.1210/en.2017-00872] [PMID: 29186342]
[http://dx.doi.org/10.1155/2019/2970401] [PMID: 30944665]
[http://dx.doi.org/10.1186/s12933-015-0197-0] [PMID: 25928419]
[http://dx.doi.org/10.1172/JCI21889] [PMID: 15546003]
[http://dx.doi.org/10.1056/NEJMe0708703] [PMID: 18199856]
[http://dx.doi.org/10.14196/mjiri.32.97] [PMID: 31024864]
[http://dx.doi.org/10.1530/ERC-16-0095] [PMID: 27754854]
[http://dx.doi.org/10.1038/srep36721] [PMID: 27830724]
[http://dx.doi.org/10.1158/1940-6207.CAPR-08-0081] [PMID: 19138981]
[http://dx.doi.org/10.1016/j.bbrc.2018.08.024] [PMID: 30098788]
[http://dx.doi.org/10.1016/j.fct.2018.09.057] [PMID: 30266318]
[http://dx.doi.org/10.1007/s12032-018-1163-y] [PMID: 29904891]
[http://dx.doi.org/10.1080/15548627.2017.1332565] [PMID: 28696138]
[http://dx.doi.org/10.1053/j.gastro.2012.02.050]
[http://dx.doi.org/10.18632/oncotarget.6783] [PMID: 26734992]
[http://dx.doi.org/10.1016/j.cellsig.2017.09.006] [PMID: 28923415]
[http://dx.doi.org/10.1016/j.bbagrm.2020.194626] [PMID: 32827753]
[http://dx.doi.org/10.1186/s13046-019-1323-8] [PMID: 31383001]