Arylquins Target Vimentin to Trigger Par-4 Secretion for Tumor Cell Apoptosis

@article{Burikhanov2014ArylquinsTV,
  title={Arylquins Target Vimentin to Trigger Par-4 Secretion for Tumor Cell Apoptosis},
  author={Ravshan Burikhanov and Vitaliy M. Sviripa and Nikhil Hebbar and Wen Zhang and W. John Layton and Adel Hamza and Chang-Guo Zhan and David S. Watt and Chunming Liu and Vivek M. Rangnekar},
  journal={Nature chemical biology},
  year={2014},
  volume={10},
  pages={924 - 926}
}
The tumor suppressor protein Par-4, which is secreted by normal cells, selectively induces apoptosis in cancer cells. We identified a 3-arylquinoline derivative, designated Arylquin 1, as a potent Par-4 secretagogue in cell cultures and mice. Mechanistically, Arylquin 1 binds to vimentin, displaces Par-4 from vimentin for secretion and triggers the efficient paracrine apoptosis of diverse cancer cells. Thus, targeting vimentin with Par-4 secretagogues efficiently induces paracrine apoptosis of… 
Regulation of Caspase-Mediated Apoptosis by the Tumor Suppressor Par-4
The Prostate Apoptosis Response-4 gene Par-4 encodes a tumor suppressor protein, which can act through a number of intrinsic and extrinsic apoptotic pathways. Extracellularly, Par-4 can interact with
Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin.
TLDR
A structure-activity study identified arylquins that promote Par-4 secretion, and an evaluation of aryLquin binding to the hERG potassium ion channel using a [(3)H]-dofetilide binding assay permitted the identification of structural features that separated this undesired activity from the desired Par- 4 secretory activity.
Chloroquine-Inducible Par-4 Secretion Is Essential for Tumor Cell Apoptosis and Inhibition of Metastasis
TLDR
It is reported that the anti-malarial drug, chloroquine (CQ), is a robust inducer of Par-4 secretion from normal cells in mice and cancer patients in a clinical trial.
Arylquin 1, a potent Par-4 secretagogue, induces lysosomal membrane permeabilization-mediated non-apoptotic cell death in cancer cells.
TLDR
Interestingly, arylquin 1 induces lysosomal membrane permeabilization (LMP), and cathepsin inhibitors and overexpression of 70-kDa heat shock protein (HSP70) markedly prevent aryLquin 1-induced cell death.
A Naturally Generated Decoy of the Prostate Apoptosis Response-4 Protein Overcomes Therapy Resistance in Tumors.
TLDR
This study identifies a prostate apoptosis response-4 (Par-4) amino-terminal fragment (PAF) that is released by diverse therapy-sensitive cancer cells following therapy-induced caspase cleavage of the tumor suppressor Par-4 protein.
Development of a novel prostate apoptosis response-4 (Par-4) protein entity with an extended duration of action for therapeutic treatment of cancer.
TLDR
It is demonstrated that the Par-4Ex protein entity, produced by using the Escherichia coli expression system suitable for large-scale production, fully retains the desirable pro-apoptotic activity of Par- 4 protein, but with ~7-fold improved biological half-life.
A journey beyond apoptosis: new enigma of controlling metastasis by pro-apoptotic Par-4
TLDR
This review will focus on the therapeutic perspective of Par-4 with a special reference to its (Par-4) virgin prospect of devastating metastasis control.
Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore
TLDR
In this review, the existing knowledge on Par-4 tumor suppressive mechanisms are summarized, the new secretory pathway that has emerged and the likely discussion on its clinical implications are highlighted.
Potential Therapeutic Agents Against Par-4 Target for Cancer Treatment: Where Are We Going?
TLDR
Molecular and drugs with the capacity to upregulate Par-4 are reviewed and be an alternative to reach this druggable target, clarifying how it can be used as a therapeutic target.
Binding-Induced Fibrillogenesis Peptides Recognize and Block Intracellular Vimentin Skeletonization against Breast Cancer.
  • Jia-Qi Fan, Yi-Jing Li, +8 authors Lei Wang
  • Medicine
    Nano letters
  • 2021
TLDR
The efficacy of BIF peptide is much higher than small molecular antimetastasis drug withaferin A (5 mg/kg) as a standard, indicating that the B IF peptide shows advantages over small molecular inhibitors in blocking the intracellular protein self-assembly.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 49 REFERENCES
The Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis
TLDR
Interestingly, extracellular Par-4 induced apoptosis by binding to the stress response protein, glucose-regulated protein-78 (GRP78), expressed at the surface of cancer cells, and activates an extrinsic pathway involving cell surface GRP78 receptor for induction of apoptosis.
Mechanisms of apoptosis by the tumor suppressor Par‐4
TLDR
A review of the domains and mechanisms by which Par‐4 orchestrates the apoptotic process in both cell culture models and in physiological settings illustrates the importance of endoplasmic reticulum‐stress and higher levels of protein kinase A in tumor cells.
Paracrine apoptotic effect of p53 mediated by tumor suppressor Par-4.
TLDR
Normal cells can be empowered by p53 activation to induce Par-4 secretion for the inhibition of therapy-resistant tumors, and specific activation of p53 in normal fibroblasts selectively induced apoptosis in p53-deficient cancer cells.
The tumor inhibitor and antiangiogenic agent withaferin A targets the intermediate filament protein vimentin.
TLDR
It is shown that WFA binds to the intermediate filament (IF) protein, vimentin, by covalently modifying its cysteine residue, which is present in the highly conserved alpha-helical coiled coil 2B domain.
Novel mechanism of apoptosis resistance in cancer mediated by extracellular PAR-4.
TLDR
A novel intracellular pathway of apoptosis mediated by NF-κB through UACA elevation, which by attenuating endoplasmic reticulum stress and GRP78 translocation to the cell surface can blunt the sensitivity of cancer cells to apoptosis.
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively
Par-4 downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy.
TLDR
These findings identify Par- 4-induced multinucleation as a mechanism of cell death in oncogene-addicted cells and establish Par-4 as a negative regulator of breast cancer recurrence.
Vimentin in cancer and its potential as a molecular target for cancer therapy
TLDR
By virtue of its overexpression in cancer and its association with tumor growth and metastasis, vimentin serves as an attractive potential target for cancer therapy; however, more research would be crucial to evaluate its specific role in cancer.
Par(-4)oxysm in breast cancer.
TLDR
Downregulation of the tumor suppressor Par-4 is identified as the key determinant in apoptosis evasion, which leads to tumor recurrence in breast cancer.
A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells
TLDR
The data suggest that celastrol is a novel Hsp 90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells.
...
1
2
3
4
5
...