Withaferin A and Celastrol Overwhelm Proteostasis
Abstract
:1. Introduction
2. Proteomic Studies of WA Action
2.1. Direct Targets of WA and Effects on Protein Expression
2.2. Protein Unfolding Induced by WA
3. Proteomic Studies with CEL—Identification of Direct Targets of CEL
4. The Cell Context Generates Targeting Specificity
5. The Primary Mechanism of Action of WA and CEL Appears to Be the Induction of Proteotoxic Stress
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Cancer Cell Line | Direct or Indirect Protein or Pathway Targets (Upregulated, Downregulated, or Post-Translationally Modified Proteins) | Refs. |
---|---|---|
U87, U251, GL26 | Akt, mTOR, p70S6K, AMPKα, tuberin | [10] |
MCF7, SUM159, SK-BR-3 | WA binds to Cys303 of β-tubulin, α- and β-tubulin | [11] |
MDA-MB-231, MCF7 | FOXO3a, Bim | [12] |
MDA-MB-231, MCF7 | Complex III, Bax, Bak | [13] |
MDA-MB-231, MCF7 | Cdk1, Cdc25B/C | [14] |
MDA-MB-231, MCF7 | STAT3 | [15] |
MDA-MB-231, MCF7 | Proteasome, autophagy | [16] |
MDA-MB-231, MCF7, T-47D | ER-α, p53 | [17] |
MDA-MB-231, MCF7, T-47D, MDA-MB-68 | p90-ribosomal S6 kinase, extracellular signal-regulated kinase 1/2 | [18] |
MDA-MB-231, MCF7, T-47D, MDA-MB-468 | Autophagy | [19] |
HCT116 | STAT3 | [20] |
HCT-116, SW-480, SW-620 | pS6K, p4E-BP1, Notch signaling | [21] |
HCT116, SW480 | Mad2, Cdc20 | [22] |
MDA-1986, JMAR, UM-SCC-2, JHU011 | Cell cycle alteration | [23] |
HepG2, SNU449 | Keap1, Nrf2 | [24] |
H358, H460 | ROS | [25] |
H358, H460 | Oxidative stress, lipid peroxidation, increased GSSG/GSH | [26] |
A549 | CAMs, Akt, NF-kB | [27] |
A549 | PI3K/Akt pathway | [28] |
U-937 | MMP, MAPK pathway | [29] |
MDS92, MDS-L, HL-60, THP-1, Jurkat, Ramos | HMOX1, LC3A/B | [30] |
MOLT-4, Jurkat, REH, K-562, HeLa, Saos-2, SP2/0 | p38-MAPK signaling, ATF-2, HSP27 | [31] |
LY-10, LY-3, SudHL-6, Ramos, Raji, Mino, Jeko | Hsp90, NF-kB | [32] |
HSC3, U-2 OS | mortalin-p53 interaction | [33] |
PC-3, DU-145, LNCaP | c-Fos, HSPA6, Hsp70, c-FLIP(L) | [34] |
Caki | STAT3 | [35] |
Caki | ROS, Bcl-2, Akt | [4] |
M14, Mel501, SK28, Lu1205 | Bcl-2, Bax | [36] |
Cancer Cell Type | Direct or Indirect Protein or Pathway Targets (Upregulated, Downregulated, or Post-Translationally Modified Proteins) | Refs. |
---|---|---|
Osteosarcoma cells | Activation of reactive oxygen species (ROS)/c-Jun N-terminal kinases (JNK) signaling | [81] |
Gastric cancer cells | Downregulation of miR-21 expression; reduced phosphorylation of Akt, mTOR, and S6K and increased phosphorylation of AMPK | [82,83,84] |
Androgen-receptor-positive prostate cancer cells | The AR/miR-101 axis; degradation of androgen receptor via HSP90 inhibition of calpain activation | [85,86,87] |
Pancreatic cancer cells | Disruption of the HSP90-CDC37 interaction by targeting CDC37 | [88,89] |
HeLa (cervical cancer) cells and in vitro studies | Inhibition of p23 | [90] |
In vitro | Interaction with the carboxy-terminal region of HSP90A | [91] |
Non-small-cell lung carcinoma, liver cancer, osteosarcoma, and hepatocellular carcinoma cells | Inhibition of mitochondrial respiratory chain (MRC) complex I and, consequently, ROS accumulation | [92,93,94,95] |
Triple-negative breast cancer and melanoma cells | Mitochondrial dysfunction and PI3K/Akt/mTOR pathway inhibition | [96,97] |
MCF-7 (breast cancer) cells | AMPK-dependent cell death; increased ROS levels; increased AMPK and p53 phosphorylation | [98] |
Breast cancer cells | Destabilization of the ErbB2 and estrogen receptors | [99,100] |
HL-60 (leukemia) cells | Inhibition of topoisomerase II | [101] |
AML cells | Mitochondrial instability, activation of caspases, and downregulation of AML1-ETO/C-KIT oncoprotein, thus inhibiting the Akt, STAT3, and Erk1/2 downstream pathways | [102] |
Hepatocellular carcinoma cells | Inhibition of STAT3/Janus kinase 2 (JAK2) | [103] |
AML cells | Inhibition of Myb | [104] |
Oral squamous cell carcinoma cells | Induction of unfolded protein response-dependent cell death, endoplasmic reticulum (ER) stress, and PERK-eukaryotic initiation factor 2 (eIF2)–activating transcription factor (ATF4)-C/EBP homology protein (CHOP) signaling | [105] |
HeLa (cervical cancer) cells | Reduction in GSK3β levels | [106] |
Glioblastoma cells | Inhibition of autophagy, accumulation of polyubiquitinated proteins, induction of the heat shock response, potentiating the heat shock response induced by HSP90 inhibition | [107] |
Prostate cancer cells | Targeting of AR, ERG, and NF-kB signaling pathways | [108,109] |
Gastric cancer cells | Upregulation of miR-146a expression, suppressing the NF-Kb activity | [110] |
Multiple myeloma and prostate cancer cells; breast cancer xenografts | Inhibition of NF-kB | [111,112,113,114,115,116,117] |
Prostate cancer cells | Downregulation of IL-6 gene expression via NF-kB inhibition | [118] |
Prostate cancer xenografts and cells | Inhibition of the proteasome system | [114,115] |
Pathway | Direct WA Target or Downregulation by WA | Protein | UniProtKB Entry Name | Role/Function | Aggregation Observed |
---|---|---|---|---|---|
Oxidative stress (NRF2) | Target | Peroxiredoxin 1 | PRDX1_HUMAN | Dual functioning thiol-specific peroxidase and molecular chaperon | No |
Target | Kelch-like ECH- associated protein 1 | KEAP1_HUMAN | Inhibitor of NRF2 | No | |
Downregulation | Glutathione peroxidase 1 | GPX1_HUMAN | Reduces hydrogen peroxide to water | No | |
Downregulation | Phospholipid hydroperoxide glutathione peroxidase | GPX4_HUMAN | Reduces phospholipid hydroperoxide | No | |
Ubiquitin- proteasome system | Target | Proteasome subunit beta type-10 | PSB10_HUMAN | Proteasome subunit involved in antigen processing | No |
Target | Proteasome subunit beta type-5 | PSB5_HUMAN | Chymotrypsin-like activity of the 20S proteasome | No | |
Target | AAA+ chaperone p97 | TERA_HUMAN | Transitional endoplasmic reticulum ATPase: involved in the transport of ubiquitinated proteins and autophagy | No | |
Target | Ubiquitin carboxyl- terminal hydrolase 14 | UBP14_HUMAN | Deubiquitinating enzyme | No | |
Target | Ubiquitin carboxyl- terminal hydrolase isozyme L5 | UCHL5_HUMAN | Deubiquitinating enzyme | Yes | |
Autophagy | Target | Histone deacetylase 6 | HDAC6_HUMAN | Deacetylation of lysine residues of histones and adapter protein | No |
Target | Phospholipase A-2- activating protein | PLAP_HUMAN | Autophagy cofactor | Yes | |
Target | WD repeat domain phosphoinositide interacting protein 2 | WIPI2_HUMAN | Formation of pre- autophagosome structures | Yes | |
Target | SNARE-associated protein Snapin | SNAPN_HUMAN | Required for biogenesis of lysosome-related organelles | No | |
Target Downregulation | Tubulin beta chain | TBB1_HUMAN | Major constituent of microtubules | No | |
Downregulation | Annexin A4 | ANXA4_HUMAN | Membrane fusion | No | |
Heat shock response | Target | Heat shock factor 1 | HSF1_HUMAN | Master regulator of the heat shock response | Yes |
Target | Heat shock protein HSP 90-alpha | HS90A_HUMAN | Maturation and structural maintenance of proteins | No | |
Target | Heat shock protein HSP 90-beta | HS90B_HUMAN | Maturation and structural maintenance of proteins | No | |
Target | DnaJ homolog subfamily A member 2 | DNJA2_HUMAN | Co-chaperone of HSP70 that stimulates ATP hydrolysis | No | |
Target | BAG family molecular chaperone regulator 2 | BAG2_HUMAN | Co-chaperone of HSP70 | No | |
Target | ER membrane protein complex subunit 9 | EMC9_HUMAN | Chaperone complex that was relatively recently discovered | No | |
Downregulation | Heat shock 70 kDa protein 13 | HSP13_HUMAN | Processing of cytosolic and secretory proteins | No | |
Downregulation | DnaJ homolog subfamily C member 10 | DJC10_HUMAN | Disulfide reductase involved in the correct folding of proteins and degradation of misfolded proteins | No | |
Downregulation | Peptidyl-prolyl cis-trans isomerase FKBP4 | FKBP4_HUMAN | Prolyl isomerase and co-chaperone activities | No | |
Isomerase and disulfide reductase | Target | Peptidyl-prolyl cis-trans isomerase D | PPID_HUMAN | Co-chaperone of HSP90 complexes | Yes |
Target | Peptidyl-prolyl isomerase domain and WD repeat-containing protein 1 | PPWD1_HUMAN | cis-trans isomerization of proline imidic peptide bonds | No | |
Target | Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 | PIN1_HUMAN | Phosphorylation-specific prolyl isomerase | No | |
Downregulation | Peptidyl-prolyl cis-trans isomerase FKBP4 | FKBP4_HUMAN | Prolyl isomerase and co-chaperone activities | No | |
Downregulation | DnaJ homolog subfamily C member 10 | DJC10_HUMAN | Disulfide reductase involved in the correct folding of proteins and degradation of misfolded proteins | No | |
ER- associated protein degradation | Target | ER degradation enhancing alpha- mannosidase-like protein 3 | EDEM3_HUMAN | Catalyzes mannose trimming from Man8GlcNAc2 to Man7GlcNAc2 | No |
Target | AAA+ chaperone p97 (VCP) | TERA_HUMAN | ATPase activity | No | |
Target | Endoplasmic Reticulum-Golgi intermediate compartment protein 3 | ERGI3_HUMAN | Transport between endoplasmic reticulum and Golgi | No | |
Target | Homocysteine-responsive endoplasmic reticulum-resident ubiquitin-like domain member 1 protein | HERP1_HUMAN | Involved in ubiquitin- dependent degradation of misfolded endoplasmic reticulum proteins | No | |
Target | Transport and Golgi organization protein 1 homolog | TGO1_HUMAN | Involved in the export process exported from the endoplasmic reticulum | No | |
Protein translation | Target | Eukaryotic translation initiation factor 5A-1 | IF5A1_HUMAN | mRNA-binding protein involved in the level of mRNA turnover, acting downstream of decapping | Yes |
Target | Eukaryotic translation initiation factor 4B | IF4B_HUMAN | Required for the binding of mRNA to ribosomes | No | |
Downregulation | Eukaryotic peptide chain release factor subunit 1 | ERF1_HUMAN | Director of termination of the nascent peptide synthesis | No | |
Downregulation | Eukaryotic translation initiation factor 3 subunit M | EIF3M_HUMAN | Responsible for the initiation of protein synthesis | No | |
Cytoskeleton functions | Target | Vimentin | VIME_HUMAN | An intermediate filament type III protein | No |
Target | Annexin A2 | ANXA2_HUMAN | A multifunctional adapter protein that is part of the actin microfilament cytoskeleton | No | |
Target | Tubulin beta | TUBB1_HUMAN | A major component of the microtubules | No | |
Cell cycle | Target | Dual specificity protein kinase TTK | TTK_HUMAN | Kinase essential for chromosome alignment | Yes |
Target | Nucleoporin Nup43 | NUP43_HUMAN | Involved in kinetochore microtubule attachment, mitotic progression, and chromosome segregation | Yes | |
Target | Protein phosphatase 1B | PPM1B_HUMAN | Phosphatase | No | |
Target | Serrate RNA effector molecule homolog | SRRT_HUMAN | Mediator between the cap- binding complex (CBC) and the primary microRNAs (miRNAs) processing machinery during cell proliferation | No | |
Target | Wings apart-like protein homolog | WAPL_HUMAN | Regulator of sister chromatid cohesion in mitosis | Yes | |
Target | Nuclear-interacting partner of ALK | NIPA_HUMAN | Controls entering mitotic phase | No | |
Target | Mini-chromosome maintenance complex-binding protein | MCMBP_HUMAN | Associated component of the MCM complex that acts as a regulator of DNA replication | Yes | |
Target | Serine/threonine- protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform | 2ABA_HUMAN | Phosphatase. The B regulatory subunit modulates substrate selectivity and catalytic activity | No | |
Protein kinase functions | Target | TTK protein kinase | TTK_HUMAN | Involved in chromosome alignment | Yes |
Target | Serine/threonine- protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform | 2AAA_HUMAN | Phosphatase. The B regulatory subunit modulates substrate selectivity and catalytic activity | No | |
Target | Serine/threonine- protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform | 2ABA_HUMAN | Phosphatase. The B regulatory subunit modulates substrate selectivity and catalytic activity | No | |
NFkB pathway | Target | Coiled-coil domain-containing protein 22 | CCD22_HUMAN | Promoting IκB ubiquitination | Yes |
Target | Activating signal co- integrator 1 complex subunit 2 | ASCC2_HUMAN | Transactivator of NFκB | No | |
Target | ELKS/Rab6- interacting/CAST family member 1 | RB6I2_HUMAN | Regulatory subunit of IKK | No | |
Target | COMM domain- containing protein 3 | COMD3_HUMAN | Downregulates activation of NFκB | Yes | |
Target | Transcription factor p65 (RelA) | TF65_HUMAN | Transcription factor | Yes | |
Target | Nuclear factor NFκB p105 subunit | NFκB1_HUMAN | DNA binding | No |
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Vilaboa, N.; Voellmy, R. Withaferin A and Celastrol Overwhelm Proteostasis. Int. J. Mol. Sci. 2024, 25, 367. https://doi.org/10.3390/ijms25010367
Vilaboa N, Voellmy R. Withaferin A and Celastrol Overwhelm Proteostasis. International Journal of Molecular Sciences. 2024; 25(1):367. https://doi.org/10.3390/ijms25010367
Chicago/Turabian StyleVilaboa, Nuria, and Richard Voellmy. 2024. "Withaferin A and Celastrol Overwhelm Proteostasis" International Journal of Molecular Sciences 25, no. 1: 367. https://doi.org/10.3390/ijms25010367