Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Lines
2.2. siRNA Transfection
2.3. Stable Repression of CFL1 Expression
2.4. In Vivo Xenograft Assays
2.5. qRT-PCR
2.6. Western Blot
2.7. BrdU Proliferation Assay
2.8. Soft Agar Assays
2.9. Flow Cytometry
2.10. Cell Tracking
2.11. Wound Healing
2.12. Boolean Network
2.13. Model Construction
2.14. Model Simulation
2.15. Perturbation Screening
2.16. Binarization of Gene Expression Data
3. Results
3.1. CFL1 Is Overexpressed in Pancreatic Cancer
3.2. CFL1 Knockdown Inhibits Proliferation and Tumor Growth
3.3. CFL1 Knockdown Does Not Induce Apoptosis
3.4. CFL1 Deficiency Leads to Distinct Defects in Cell Migration
3.5. Establishing a Model to Uncover Mechanistic Regulation of CFL1
3.6. Ras-Induced Imbalance in Actin Remodeling Leads to Overexpressed and Activated CFL1
3.7. The Synergy between CFL1 and Arp2/3 Is Important for Migration
3.8. CFL1 Influences the Cell Cycle via STAT3
3.9. Mitochondrial CFL1 and Its Downstream Targets Influence Apoptosis Regulation
3.10. Systematic Perturbation Screening Identified Targets to Induce Apoptosis in the Model
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Node; t + 1 | Boolean Function, t | References |
---|---|---|
TCF7L2 | PRKD1 | PRKD1 inhibits TCF7L2 expression [11]. |
AURKA | PAK1 | PAK1 phosphorylates AURKA [47,48,49]. |
Phosphorylated-CFL1 | CD44 TCF7L2 (CFL1 LIMK SSH1L) | TCF7L2 activates CFL1 expression [11]. CD44 induces CFL1 expression [50,51]. LIMK inhibits CFL1 [52,53,54,55,56,57]. If both, SSH1L and LIMK are active, CFL1 stays unphosphorylated [58,59,60]. |
CFL1 | (SSH1L Phosphorylated-CFL1) (SSH1L LIMK Phosphorylated-CFL1) | SSH1L dephosphorylates CFL1 [12,52,53,54,56,57,58,61]. LIMK phosphorylates CFL1 [12,52,53,56,58]. If SSH1L and LIMK are present, LIMK may restore phosphorylation, but the dephosphorylation of SSH1L is more pronounced [58,59,60]. |
CD44 | TWIST1 | TWIST1 upregulates CD44 [62,63]. |
TWIST1 | AURKA | AURKA inhibits degradation of TWIST1 [63]. |
LIMK | (RHOA PAK1 PAK4) SSH1L | LIMK is activated by dephosphorylation of PAK1, PAK4 and ROCK (downstream of RHOA) [48,53,55,59,61,64,65,66]. LIMK and SSH1L can build a complex that effectively dephosphorylates both [59,60]. |
SSH1L | ((F-actinnew F-actinold) PRKD1) (PI3K AURKA) (LIMK SSH1L) | F-actin enhances SSH1L activity [52,57,59,61]. PRKD1 phosphorylates SSH1L [52,53,61]. In the presence of PI3K, AURKA induces SSH1L expression [54,56,57]. LIMK and SSH1L can build a complex that effectively dephosphorylates both [59,60]. |
F-actinnew | (CFL1 ARP2/3) (RHOA(-3) CFL1) | CFL1 and ARP2/3 work in synergy to create new branched actin fibres [58,67,68,69,70,71,72]. RHOA/ROCK/DIA pathway polymerizes F-actin (here RHOA delay) [64,73,74,75]. |
F-actinold | (F-actinold CFL1) F-actinnew | CFL1 severs F-actin [52,65,67] preferring old ADP-F-actin [58,68,76,77]. Newly formed actin fibres are built, prolonged and thus converted into old ones. |
ARP2/3 | RAC1(-2) | Downstream of RAC1, ARP2/3 is activated by WAVE or WASP (here by a RAC1 delay) [58,64,69]. |
KRAS | 1 | Activating KRAS mutations are present in more than 90% of PDAC patients [3,46,78,79]. For this reason, the protein KRAS is assumed to be always active. Therefore, we modeled it as active (1). |
PI3K | KRAS CD44 | The PI3K-pathway is one of the main effector pathways downstream of RAS [80]. CD44 receptor binding activates PI3K/AKT pathway [62,81,82]. |
PRKD1 | RHOA | RHOA activates PRKD1 [11,52,53,65]. |
RHOA | PAK4 | PAK4 inhibits RHOA [83]. |
RAC1 | PI3K Phorsphorylated-CFL1(-3) | RAC1 is activated by PI3K [54,80,84]. Phosphorylated CFL1 activates RAC1 via PLD1 and DOCK (here with delay) [85]. |
PAK1 | RAC1 | PAK1 is activated by RAC1 [47,48,55,86,87]. |
PAK4 | RAC1 | PAK4 is activated by RAC1 [47,48,55]. |
CDH1 | TWIST1 | TWIST1 inhibits CDH1 expression [63,88,89,90,91]. |
CTNNB1 | PAK1 PRKD1 CDH1 | PAK1 stabilizes CTNNB1 [48,55,86,87]. CDH1 blocks CTNNB1 entering the nucleus [91,92,93,94]. PRKD1 inhibits CTNNB1 expression [11]. |
GSK3B | AKT | AKT inactivates GSK3B [56,80,95,96,97]. |
MYC | (GSK3B STAT3) (CTNNB1 GSK3B) | STAT3 induces MYC expression [56,98,99,100,101,102]. GSK3B ubiquitinates MYC [103]. GSK3B blocks expression of MYC by CTNNB1 [55,94,104,105]. |
CCND1 | (GSK3B MYC AKT) | GSK3B destabilizes CCND1 [96,97]. AKT supports the assembly of CCND1 with CDK4/6 [97,106,107,108,109,110]. MYC induces CCND1 expression [95,110,111,112]. |
RB | CCND1 | CCND1 inhibits RB [95,96,113]. |
E2F | RB | RB inhibits E2F [95,96,113]. |
CCNE1 | E2F | E2F induces the expression of CCNE1 [95,96]. |
S-phase | E2F CCNE1 | The synergy of CCNE1 and E2F is responsible for S-phase transition [95,96,103]. |
AKT | PI3K STAT3 | PI3K activates AKT [54,96,106,110,114]. STAT3 induces expression and activation of AKT [98,115,116,117]. |
STAT3 | (Phosphorylated-CFL1 CFL1) CD44 | CFL1 regulates amount of STAT3 [45]. CD44 activates STAT3 [56,118]. |
Anti-apoptotic proteins | STAT3 | STAT3 induces expression of BCL2L1 or MCL1 [99,100,101,102,119]. |
Pro-apoptotic proteins | AKT | AKT phosphorylates BAD [119,120,121]. |
CYCS | Pro-apoptotic proteins Anti-apoptotic proteins CFL1 | Imbalance between pro- and anti-apoptotic proteins induce release of CYCS by activating BAX. Unphosphorylated CFL1 translocates to the mitochondrion after induction of apoptosis [122,123,124,125] and acts as a carrier for BAX [126]. |
Caspases | CYCS AKT | Released CYCS forms an apoptosome further activating caspases signalling [119,120,122,124,127,128,129]. AKT phosphorylates caspase-9 [119,120,121]. |
Associated Behavior | Model-Based Phenotypical Description (Attractor) | Validation | |
---|---|---|---|
Literature | Wet Lab/Dataset Analyses | ||
Overexpression of active CFL1 | PRKD1 (inactive) | [130,131] | |
TCF7L2 (active) | GSE15471, GSE16515, GSE32676 (see Figure 4b) | ||
AURKA (active) | GSE15471, GSE16515, GSE32676 (see Figure 4a) | ||
SSH1L (active) | [61] | ||
Invasion | KRAS (active) | [3,46,78,79] | |
RAC1 (active) | [132] | ||
ARP 2/3 (active) | [133,134] | ||
F-actinnew (active) | [135,136] | Time lapse Figure 2b | |
Proliferation | STAT3 (active) | Western blot Figure 4d | |
AKT (active) | [137,138] | ||
MYC (active) | Western blot Figure 4d | ||
CCND1 (active) | Western blot Figure 4d | ||
Survival | AKT (active) | [137,138] | |
STAT3 (active) | Western blot Figure 4d | ||
Anti-apoptotic proteins (active) | GSE15471, GSE16515, GSE32676 (see Figure 4e) | ||
Caspases (inactive) | Western blot Figure 2a |
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Werle, S.D.; Schwab, J.D.; Tatura, M.; Kirchhoff, S.; Szekely, R.; Diels, R.; Ikonomi, N.; Sipos, B.; Sperveslage, J.; Gress, T.M.; et al. Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer. Cancers 2021, 13, 725. https://doi.org/10.3390/cancers13040725
Werle SD, Schwab JD, Tatura M, Kirchhoff S, Szekely R, Diels R, Ikonomi N, Sipos B, Sperveslage J, Gress TM, et al. Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer. Cancers. 2021; 13(4):725. https://doi.org/10.3390/cancers13040725
Chicago/Turabian StyleWerle, Silke D., Julian D. Schwab, Marina Tatura, Sandra Kirchhoff, Robin Szekely, Ramona Diels, Nensi Ikonomi, Bence Sipos, Jan Sperveslage, Thomas M. Gress, and et al. 2021. "Unraveling the Molecular Tumor-Promoting Regulation of Cofilin-1 in Pancreatic Cancer" Cancers 13, no. 4: 725. https://doi.org/10.3390/cancers13040725