Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells

Int J Mol Sci. 2019 May 22;20(10):2518. doi: 10.3390/ijms20102518.


The endoplasmic reticulum (ER) has diverse functions, and especially misfolded protein modification is in the focus of this review paper. With a highly regulatory mechanism, called unfolded protein response (UPR), it protects cells from the accumulation of misfolded proteins. Nevertheless, not only does UPR modify improper proteins, but it also degrades proteins that are unable to recover. Three pathways of UPR, namely PERK, IRE-1, and ATF6, have a significant role in regulating stress-induced physiological responses in cells. The dysregulated UPR may be involved in diseases, such as atherosclerosis, heart diseases, amyotrophic lateral sclerosis (ALS), and cancer. Here, we discuss the relation between UPR and cancer, considering several aspects including survival, dormancy, immunosuppression, angiogenesis, and metastasis of cancer cells. Although several moderate adversities can subject cancer cells to a hostile environment, UPR can ensure their survival. Excessive unfavorable conditions, such as overloading with misfolded proteins and nutrient deprivation, tend to trigger cancer cell death signaling. Regarding dormancy and immunosuppression, cancer cells can survive chemotherapies and acquire drug resistance through dormancy and immunosuppression. Cancer cells can also regulate the downstream of UPR to modulate angiogenesis and promote metastasis. In the end, regulating UPR through different molecular mechanisms may provide promising anticancer treatment options by suppressing cancer proliferation and progression.

Keywords: ATF6; IRE-1; PERK; cancer; endoplasmic reticulum (ER); unfolded protein response (UPR).

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Survival
  • Disease Progression
  • Humans
  • Immune Tolerance
  • Neoplasm Metastasis / immunology
  • Neoplasm Metastasis / pathology
  • Neoplasm Metastasis / therapy
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / therapy
  • Unfolded Protein Response*