The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling
Abstract
1. Introduction
2. Genetic Aberrations in the PI3K-AKT-mTOR Pathway in Prostate Cancer Are Diverse
2.1. PI3K Gain of Function
2.1.1. Class IA PI3Ks
2.1.2. Class IB PI3Ks
2.1.3. Class II PI3Ks
2.1.4. Class III PI3Ks
2.2. Loss of Function of Phosphoinositide Phosphatases
2.2.1. Loss or Inactivation of PTEN
2.2.2. Deregulation of Phosphoinositide Phosphatase Enzymes (other than PTEN)
2.3. AKT Gain of Function
2.3.1. AKT Mutation and Amplification
2.3.2. Genetic Alteration of AKT Regulators
2.4. SGK Deregulation
2.5. Loss of FOXO Transcription Factors
2.6. TSC1-TSC2-TBC1D7 Complex and RHEB Deregulation
2.7. Amplification of mTORC1 and mTORC2 Complex Components
2.8. Aberrant AMPK Signaling
2.8.1. CAMKKβ Amplification
2.8.2. LKB1 Loss
2.8.3. Sestrin Deletion
2.8.4. MAP3K7 Deletion
3. The PI3K-AKT-mTOR Pathway Intersects with Multiple Oncogenic Signaling Cascades to Facilitate Prostate Cancer Growth
3.1. PI3K-AKT-mTOR and RAS/MAPK Signaling Crosstalk
3.1.1. RAS/MAPK-PI3K-AKT-mTOR Interactions Promote Resistance to PI3K-AKT-mTOR Pathway-Directed Therapies
3.1.2. Co-targeting RAS/MAPK and PI3K-AKT-mTOR Signaling in Prostate Cancer
3.2. PI3K-AKT-mTOR and AR Signaling Crosstalk
3.3. PI3K-AKT-mTOR and WNT Signaling Interactions
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
3β-HSD | 3β hydroxysteroid dehydrogenase |
4E-BP1 | Eukaryotic translation initiation factor 4E binding protein 1 |
ADT | Androgen deprivation therapy |
AD | Androstenedione |
AGC | cAMP-dependent, cGMP-dependent and protein kinase C |
AKTi | AKT inhibitor |
AMP | Adenosine monophosphate |
AMPK | 5′ AMP-activated protein kinase |
APC | Adenomatous polyposis coli |
AR | Androgen receptor |
ARE | Androgen responsive element |
ARF1 | Adenosine ribosylation factor 1 |
ATG14 | Autophagy related 14 homolog |
ATP | Adenosine triphosphate |
AXIN | Axis inhibitor protein |
BAD | Bcl-2-associated death promoter |
BMK-1 | Big mitogen-activated protein kinase-1 |
CaMKII | Calmodulin-dependent kinase 2 |
CAMKKβ | Ca(2+)/calmodulin-dependent protein kinase kinase β |
CAV1 | Caveolin-1 |
CDK4 | Cyclin-dependent kinase 4 |
c-JUN | Transcription factor AP-1 |
CK1 | Casein kinase 1 |
CAN | Copy number alteration |
CREB | cAMP response element-binding protein |
CRPC | Castrate resistant prostate cancer |
CYP17A1 | Cytochrome P450 17A1 |
DEPTOR | Dishevelled, EGL-10 and pleckstrin (DEP) domain-containing mTOR-interacting protein |
DFCI | Dana-Farber Cancer Institute |
DHEA | Dehydroepiandrosterone |
DHTDVL | DihydrotestosteroneDisheveled |
EIF4E | Eukaryotic translation initiation factor 4E |
EGF | Epidermal growth factor |
EGFR | Epidermal growth factor receptor |
EGR1 | Early growth response 1 |
EMT | Epithelial-to-mesenchymal transition |
ERG1 | ETS-related Gene 1 |
ERK1 | Mitogen-activated protein kinase 3 |
ERK2 | Mitogen-activated protein kinase 1 |
EZH2 | Enhancer of zeste homolog 2 |
FKBP5 | FK506 binding protein 5 |
FOXO | Forkhead box protein O |
FGFR | Fibroblast growth factor receptor |
FZD | Frizzled family receptor |
GAB1 | GRB2-associated binder-1 |
GDP | Guanosine diphosphate |
GLUT3 | Glucose transporter 3 |
GnRH | Gonadotrophin-releasing hormone |
GPCR | G-protein coupled receptor |
GR | Glucocorticoid receptor |
GRB2 | Growth factor receptor-bound protein 2 |
GRB10 | Growth factor binding protein 10 |
GSK3β | Glycogen synthase kinase 3 beta |
GTP | Guanosine triphosphate |
HDAC3 | Histone deacetylase 3 |
HER2/3 | Human epidermal growth factor receptor 2/3 |
HSD3B/17B3 | Hydroxysteroid dehydrogenase 3B/17B3 |
HSP70/90 | Heat shock protein 70/90 |
IGF | Insulin growth factor |
IGF-1 | Insulin growth factor 1 |
IHC | Immunohistochemistry |
IL6 | Interleukin 6 |
INPP4B | Inositol polyphosphate 4-phosphatase type II |
INPP5D | Inositol polyphosphate-5-phosphatase D |
INPP5J | Inositol polyphosphate-5-phosphatase J |
INPPL1 | Inositol polyphosphate phosphatase like 1 |
IRS | Insulin receptor substrate |
IRS1 | Insulin receptor substrate protein 1 |
KLK3 | Kallikrein related peptidase 3 |
LAT1/2/3 | L-type amino acid transporter 1/2/3 |
LDHA | L-lactate dehydrogenase A chain |
LEF | Lymphoid enhancer binding factor |
LH | Luteinizing hormone |
LHRH | Luteinizing hormone-releasing hormone |
LKB1 | Liver kinase B1 |
LRP5/6 | Low-density lipoprotein receptor-related proteins 5 and 6 |
MAPK | Mitogen-activated protein kinase |
MAP3K7 | Mitogen-activated protein kinase kinase kinase 7 |
mCRPC | Metastatic castrate resistant prostate cancer |
MDM2 | Mouse double minute 2 homolog |
MEK | Mitogen-activated protein kinase kinase |
MSKCC | Memorial Sloan Kettering Cancer Centre |
mLST8 | MTOR associated protein LST8 homolog |
MMTV-PyMT | Mouse mammary tumor virus-polyoma middle tumor-antigen |
MNK1 | MAP kinase interacting serine/threonine kinase 1 |
MNK2 | MAP kinase interacting serine/threonine kinase 2 |
mSIN1 | Mitogen-activated protein kinase associated protein 1 (MAPKAP1) |
mTOR | Mammalian target of rapamycin |
mTORC1 | Mammalian target of rapamycin complex 1 |
mTORC1i | mTORC1 inhibitor |
mTORC2 | Mammalian target of rapamycin complex 2 |
MuSK | Muscle specific kinase |
NF-κB | Nuclear factor kappa light chain enhancer of activated B cells |
NKX3.1 | NK3 Homeobox 1 |
NSCLC | Non-small-cell lung carcinoma |
P | Phosphorylation event |
PDK1 | Phosphoinositide-dependent kinase 1 |
PGC-1α | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
PHLPP | PH domain leucine-rich repeat protein phosphatase |
PHLPP1 | PH domain and leucine rich repeat protein phosphatase 1 |
PHLPP2 | PH domain and leucine rich repeat protein phosphatase 2 |
PI | Phosphatidylinositol |
PI3K | Phosphoinositide 3-kinase |
PI(3)P | Phosphatidylinositol 3-phosphate |
PI(3,4)P2 | Phosphatidylinositol 3,4-bisphosphate |
PIN | Prostate intra-epithelial neoplasia |
PIP2 | Phosphatidylinositol 4,5-bisphosphate |
PIP3 | Phosphatidylinositol 3,4,5-trisphosphate |
PIPP | Proline-rich inositol polyphosphate 5-phosphatase |
PKB | Protein kinase B, AKT |
PKC | Protein kinase |
PKCα | Protein kinase C alpha |
PLC | Phospholipase C |
PP2A | Protein phosphatase 2A |
PPP2CA | Protein phosphatase 2 catalytic subunit Alpha |
PRAS40 | Proline-rich AKT substrate of 40 kDa |
PROTOR1 | Protein observed with Rictor-1 |
PROTOR2 | Protein observed with Rictor-2 |
PSA | Prostate specific antigen |
PTEN | Phosphatase and tensin homologue deleted on chromosome 10 |
PTK7 | Protein tyrosine kinase 7 |
RAF | Rapidly accelerated fibrosarcoma |
RAG | Recombination activating genes |
RAPTOR | Regulatory-associated protein of mTOR |
RBD | Ras-binding domain |
RHEB | Ras homolog enriched in brain |
RICTOR | Rapamycin-insensitive companion of mTOR |
ROR1/2 | Receptor tyrosine kinase–like orphan receptor-1 and -2 |
RPS6 | Ribosomal protein S6 |
rPFS | Radiographic progression-free survival |
RSK | 90 kDa Ribosomal S6 kinase |
RTK | Tyrosine kinase receptor |
RYK | Receptor-like tyrosine kinase |
S6K | Ribosomal protein S6 kinase/p70 ribosomal S6 kinase |
SESN1 | Sestrin 1 |
SGK1 | Serum and glucocorticoid regulated kinase 1 |
SGK2 | Serum and glucocorticoid regulated kinase 2 |
SGK3 | Serum and glucocorticoid regulated kinase 3 |
SH2 | Src homology 2 |
SHIP1 | SH2 domain-containing inositol 5′-phosphatase 1 |
SHIP2 | SH2 domain-containing inositol 5′-Phosphatase 2 |
SLC2A3 | Solute carrier family 2, facilitated glucose transporter member 3 |
SLC43A1 | Solute carrier family 43 member 1 |
SOS | Son of Sevenless |
SPOP | Speckle type BTB/POZ protein |
SRC-3 | Steroid receptor co-activator 3 |
SRF | Serum response factor |
SU2C-PCF IDT | Stand Up To Cancer & Prostate Cancer Foundation International Dream Team |
T | Testosterone |
TAK1 | TGFβ-activated kinase 1 |
TAZ | Transcriptional coactivator with PDZ binding motif |
TBC1D7 | TBC1 Domain Family Member 7 |
TCF | T cell Factor |
TCGA | The Cancer Genome Atlas |
TEAD | Transcriptional enhanced associate domain |
TEL2 | Telomere length regulation protein |
TGF | Transforming growth factor |
TMPRSS2-ERG | Transmembrane protease, serine 2: ETS Transcription Factor fusion |
TRAMP | Transgenic adenocarcinoma mouse prostate |
TSC1 | Tuberous Sclerosis complex 1 |
TSC2 | Tuberous Sclerosis complex 2 |
TTI1 | TELO2 interacting protein 1 |
Ub | Ubiquitination event |
ULK1 | Unc-51 Like Autophagy Activating Kinase 1 |
UVRAG | UV radiation resistance-associated gene; v-ATPase, Vacuolar (H+)-ATPase |
VPS15 | Vacuolar protein sorting 15 |
V-ATPase | Vacuolar H+-ATPase |
WNT | WNT ligand |
YAP | Yes-associated protein |
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Common Types of Genetic Alterations in PI3K-AKT-mTOR Pathway Genes | Frequency in Prostate Cancer 1 |
---|---|
PTEN deletion/mutation | 16.4–32.0% |
DEPTOR amplification | 5.1–21.4% |
SGK mutation/amplification | 5.6–20.5% (SGK3) |
0.2–2.7% (SGK1) | |
FOXO deletion | 0.0–15.2% (FOXO1) |
4.5–13.4% (FOXO3) | |
MAP3K7 deletion | 5.9–14.8% |
RRAGD deletion | 6.5–14.4% |
SESN1 mutation/deletion | 5.4–13.6% |
PIK3CA mutation/amplification | 5.5–11.5% |
PIK3C2B mutation/amplification | 1.4–11.5% |
PDPK1 amplification | 0–8.1% |
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Shorning, B.Y.; Dass, M.S.; Smalley, M.J.; Pearson, H.B. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. Int. J. Mol. Sci. 2020, 21, 4507. https://doi.org/10.3390/ijms21124507
Shorning BY, Dass MS, Smalley MJ, Pearson HB. The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. International Journal of Molecular Sciences. 2020; 21(12):4507. https://doi.org/10.3390/ijms21124507
Chicago/Turabian StyleShorning, Boris Y., Manisha S. Dass, Matthew J. Smalley, and Helen B. Pearson. 2020. "The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling" International Journal of Molecular Sciences 21, no. 12: 4507. https://doi.org/10.3390/ijms21124507
APA StyleShorning, B. Y., Dass, M. S., Smalley, M. J., & Pearson, H. B. (2020). The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. International Journal of Molecular Sciences, 21(12), 4507. https://doi.org/10.3390/ijms21124507