Discovery and Overview of Par-4

Saptadwipa Ganguly, Ravshan Burikhanov, Shirley Qiu, Vivek M. Rangnekar

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review


Prostate apoptosis response-4 (Par-4) is a tumor suppressor that was first identified as an immediate early gene in a differential screen for genes induced during the process of apoptosis in prostate cancer cells. Par-4 is ubiquitously expressed in normal human and rodent cells and tissues but is downregulated, mutated, or inactivated in most cancer cells. Functionally, elevated levels of Par-4 induce apoptosis in cancer cells and experimental tumors or sensitize normal and cancer cells to the apoptotic action of diverse insults. Par-4 contains several functional domains, including a leucine zipper domain at the carboxy terminus, selective for apoptosis of cancer cells (SAC) domain naturally placed in the center of the molecule, and Par-4 amino-terminal fragment, which regulate its tumor suppressor and pro-apoptosis function. Par-4 is a unique tumor suppressor protein expressed both intracellularly in the cytoplasm and nucleus and extracellularly. Protein kinase A activates intracellular Par-4 by phosphorylation at Thr155 residue in rat Par-4 or Thr163 in human Par-4. Activated intracellular Par-4 induces the Fas (CD95)/FasL apoptotic pathway and also inhibits NF-κB cell survival pathway. On the other hand, Akt1 inactivates Par-4 by phosphorylation at S249 in rat Par-4 or S228 in human Par-4. Extracellular Par-4 acts via cell surface receptor glucose-regulated protein 78 (GRP78) to induce caspase-8/caspase-3 and apoptosis. Whether intracellular or extracellular, Par-4 induces cancer-selective apoptosis without harming normal cells, making Par-4 an attractive target in cancer therapy. Moreover, Par-4 plays key roles in epithelial mesenchymal transition, inflammation, neuronal degenera-tion, diabetes, and cardiac and retinal apoptosis. In recent years, FDA-approved drugs and new compounds that can stimulate secretion of Par-4 from normal cells of the body to induce paracrine apoptosis of cancer cells have been identified, and clinical trials are ongoing. Thus, Par-4 research has progressed from the bench to the bedside to impact the longevity of cancer patients. This chapter provides a succinct description of research on the discovery of Par-4, leading to its key domains, interactive partners, and regulation along with mechanistic evidence supporting Par-4 function.

Original languageEnglish
Title of host publicationTumor Suppressor Par-4
Subtitle of host publicationStructural Features, Molecular Mechanisms and Function
Number of pages59
ISBN (Electronic)9783030735722
StatePublished - Jan 1 2022

Bibliographical note

Publisher Copyright:
© Springer Nature Switzerland AG 2022.


  • Apoptosis
  • Atypical protein kinase Cζ (ζPKC)
  • B)
  • CK2
  • Crystallography
  • EMT
  • ER stress
  • FBOX45
  • GRP78
  • Glucose-regulated protein 78 (GRP78)
  • Inflammation
  • Leucine zipper (LZ) domain
  • Neurodegeneration
  • Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-
  • Nuclear localization signal (NLS)
  • PAWR
  • PKA
  • PLK1
  • Par-4 amino-terminal fragment (PAF)
  • Pluripotent stem cells
  • Prostate apoptosis response-4 (Par-4)
  • RASS2
  • Ras
  • Secretagogues
  • Selective for apoptosis in cancer cells (SAC)
  • Tumor suppressor
  • Ubiquitin
  • c-Myc
  • wilm’s tumor protein 1 (WT1)

ASJC Scopus subject areas

  • General Medicine


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