Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Mutant p53 improves cancer cells’ resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6

Oncogene volume 38, pages 6184–6195 (2019)Cite this article

Subjects

Abstract

Missense mutations in the TP53 gene are frequent in human cancers, giving rise to mutant p53 proteins that can acquire oncogenic properties. Gain of function mutant p53 proteins can enhance tumour aggressiveness by promoting cell invasion, metastasis and chemoresistance. Accumulating evidences indicate that mutant p53 proteins can also modulate cell homeostatic processes, suggesting that missense p53 mutation may increase resistance of tumour cells to intrinsic and extrinsic cancer-related stress conditions, thus offering a selective advantage. Here we provide evidence that mutant p53 proteins can modulate the Unfolded Protein Response (UPR) to increase cell survival upon Endoplasmic Reticulum (ER) stress, a condition to which cancer cells are exposed during tumour formation and progression, as well as during therapy. Mechanistically, this action of mutant p53 is due to enhanced activation of the pro-survival UPR effector ATF6, coordinated with inhibition of the pro-apoptotic UPR effectors JNK and CHOP. In a triple-negative breast cancer cell model with missense TP53 mutation, we found that ATF6 activity is necessary for viability and invasion phenotypes. Together, these findings suggest that ATF6 inhibitors might be combined with mutant p53-targeting drugs to specifically sensitise cancer cells to endogenous or chemotherapy-induced ER stress.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2:326–32.

    Article  CAS  Google Scholar 

  2. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334:1081–6.

    Article  CAS  Google Scholar 

  3. Prischi F, Nowak PR, Carrara M, Ali MMU. Phosphoregulation of Ire1 RNase splicing activity. Nat Commun. 2014;5:3554.

    Article  Google Scholar 

  4. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, et al. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000;287:664–6.

    Article  CAS  Google Scholar 

  5. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature. 1999;397:271–4.

    Article  CAS  Google Scholar 

  6. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 2004;11:381–9.

    Article  CAS  Google Scholar 

  7. Haze K, Yoshida H, Yanagi H, Yura T, Mori K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell. 1999;10:3787–99.

    Article  CAS  Google Scholar 

  8. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi M, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol. 2000;20:6755–67.

    Article  CAS  Google Scholar 

  9. Wu J, Rutkowski DT, Dubois M, Swathirajan J, Saunders T, Wang J, et al. ATF6alpha optimizes long-term endoplasmic reticulum function to protect cells from chronic stress. Dev Cell. 2007;13:351–64.

    Article  CAS  Google Scholar 

  10. Chevet E, Hetz C, Samali A. Endoplasmic reticulum stress–activated cell reprogramming in oncogenesis. Cancer Discov. 2016;5:586–97.

    Article  Google Scholar 

  11. Clarke Hanna J, Chambers Joseph E, Liniker E, Marciniak Stefan J. Endoplasmic reticulum stress in malignancy. Cancer Cell. 2014;25:563–73.

    Article  CAS  Google Scholar 

  12. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer. 2014;14:581–97.

    Article  CAS  Google Scholar 

  13. Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2:252–62.

    Article  Google Scholar 

  14. Senft D, Ronai AZe. Adaptive stress responses during tumor metastasis and dormancy. Trends Cancer. 2016;2:429–42.

    Article  Google Scholar 

  15. Kim MP, Lozano G. Mutant p53 partners in crime. Cell Death Differ. 2018;25:161–8.

    Article  CAS  Google Scholar 

  16. Sabapathy K, Lane DP. Therapeutic targeting ofp53: All mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15:13–30.

    Article  CAS  Google Scholar 

  17. Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26:199–212.

    Article  Google Scholar 

  18. Cooks T, Pateras IS, Tarcic O, Solomon H, Schetter AJ, Wilder S, et al. Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell. 2013;23:634–46.

    Article  CAS  Google Scholar 

  19. Di Minin G, Bellazzo A, Dal Ferro M, Chiaruttini G, Nuzzo S, Bicciato S, et al. Mutant p53 reprograms TNF signaling in cancer cells through interaction with the tumor suppressor DAB2IP. Mol Cell. 2014;56:617–29.

    Article  Google Scholar 

  20. Ingallina E, Sorrentino G, Bertolio R, Lisek K, Zannini A, Azzolin L, et al. Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis. Nat Cell Biol. 2018;20:28–35.

    Article  CAS  Google Scholar 

  21. Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol. 2016;18:897–909.

    Article  CAS  Google Scholar 

  22. Vogiatzi F, Brandt DT, Schneikert J, Fuchs J, Grikscheit K, Wanzel M, et al. Mutant p53 promotes tumor progression and metastasis by the endoplasmic reticulum UDPase ENTPD5. Proc Natl Acad Sci USA. 2016;113:E8433–42.

    Article  CAS  Google Scholar 

  23. Wang Y, Shen J, Arenzana N, Tirasophon W, Kaufman RJ, Prywes R. Activation of ATF6 and an ATF6 DNA binding site by the endoplasmic reticulum stress response. J Biol Chem. 2000;275:27013–20.

  24. Montibeller L, de Belleroche J. Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) are characterised by differential activation of ER stress pathways: focus on UPR target genes. Cell Stress Chaperones. 2018;23:897–912.

    Article  CAS  Google Scholar 

  25. Silwal-Pandit L, Vollan HKM, Chin SF, Rueda OM, McKinney S, Osako T, et al. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance. Clin Cancer Res. 2014;20:3569–80.

    Article  CAS  Google Scholar 

  26. Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, et al. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 2018;173:400–16 e11.

    Article  CAS  Google Scholar 

  27. Adachi Y, Yamamoto K, Okada T, Yoshida H, Harada A, Mori K. ATF6 is a transcription factor specializing in the regulation of quality control proteins in the endoplasmic reticulum. Cell Struct Funct. 2008;33:75–89.

    Article  CAS  Google Scholar 

  28. Li D, Marchenko ND, Moll UM. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 2011;18:1904–13.

    Article  CAS  Google Scholar 

  29. Guan M, Fousek K, Jiang C, Guo S, Synold T, Xi B, et al. Nelfinavir induces liposarcoma apoptosis through inhibition of regulated intramembrane proteolysis of SREBP-1 and ATF6. Clin Cancer Res. 2011;17:1796–806.

    Article  CAS  Google Scholar 

  30. Guan M, Su L, Yuan Y-C, Li H, Chow WA. Nelfinavir and nelfinavir analogs block site-2 protease cleavage to inhibit castration-resistant prostate cancer. Sci Rep. 2015;5:9698.

    Article  CAS  Google Scholar 

  31. Gallagher CM, Walter P. Ceapins inhibit ATF6α signaling by selectively preventing transport of ATF6α to the Golgi apparatus during ER stress. eLife. 2016;5:1–24.

    CAS  Google Scholar 

  32. Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharm Rev. 2006;58:621–81.

    Article  CAS  Google Scholar 

  33. Ogata M, Hino S-i, Saito A, Morikawa K, Kondo S, Kanemoto S, et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26:9220–31.

    Article  CAS  Google Scholar 

  34. Tay KH, Luan Q, Croft A, Jiang CC, Jin L, Zhang XD, et al. Sustained IRE1 and ATF6 signaling is important for survival of melanoma cells undergoing ER stress. Cell Signal. 2014;26:287–94.

    Article  CAS  Google Scholar 

  35. Zeng L, Lu M, Mori K, Luo S, Lee AS, Zhu Y, et al. ATF6 modulates SREBP2-mediated lipogenesis. EMBO J. 2004;23:950–8.

    Article  CAS  Google Scholar 

  36. Yao X, Liu H, Zhang X, Zhang L, Li X, Wang C, et al. Cell surface GRP78 accelerated breast cancer cell proliferation and migration by activating STAT3. PLoS ONE. 2015;10:e0125634.

    Article  Google Scholar 

  37. Schewe DM, Aguirre-Ghiso JA. ATF6alpha-Rheb-mTOR signaling promotes survival of dormant tumor cells in vivo. Proc Natl Acad Sci USA. 2008;105:10519–24.

    Article  CAS  Google Scholar 

  38. Li C, Fan Q, Quan H, Nie M, Luo Y, Wang L. The three branches of the unfolded protein response exhibit differential significance in breast cancer growth and stemness. Exp Cell Res. 2018;367:170–85.

    Article  CAS  Google Scholar 

  39. Bourougaa K, Naski N, Boularan C, Mlynarczyk C, Candeias MM, Marullo S, et al. Endoplasmic reticulum stress induces G2 cell-cycle arrest via mRNA translation of the p53 isoform p53/47. Mol Cell. 2010;38:78–88.

    Article  CAS  Google Scholar 

  40. Namba T, Chu K, Kodama R, Byun S, Yoon KW, Hiraki M, et al. Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1alpha/XBP1 pathway. Oncotarget. 2015;6:19990–20001.

    Article  Google Scholar 

  41. Cunha DA, Igoillo-Esteve M, Gurzov EN, Germano CM, Naamane N, Marhfour I, et al. Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human beta-cell apoptosis. Diabetes. 2012;61:2763–75.

    Article  CAS  Google Scholar 

  42. Puthalakath H, O’Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129:1337–49.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Giada Pastore (LNCIB, Trieste) for assistance with tissue culture. We thank Ciara Gallagher and Peter Walter (UCSF, USA) for kindly providing Ceapin-A7. We thank all people from LNCIB (Trieste) for advice and discussion. This work was funded by AIRC (Italian Association for Cancer Research) Investigator Grant (IG 14173) to LC, and AIRC Special Program Molecular Clinical Oncology “5 per mille” (Grant no. 10016) to GDS. This work was also funded by Regione FVG (LR 17/2014; project acronym RIFT) to GDS. AB was supported by a “G. Lucatello e G. Mazzega” postdoctoral fellowship from FIRC (Fondazione Italiana Ricerca sul Cancro), and by a Fondazione Umberto Veronesi postdoctoral fellowship. MF was supported by a “L. Fontana and M. Lionello” fellowship from FIRC. EV was supported by a “G. Lucatello e G. Mazzega” postdoctoral fellowship from FIRC.

Author information

Authors and Affiliations

  1. National Laboratory CIB (LNCIB), AREA Science Park, 34149, Trieste, Italy

    Daria Sicari, Marco Fantuz, Arianna Bellazzo, Elena Valentino, Mattia Apollonio, Ilaria Pontisso, Francesca Di Cristino, Giannino Del Sal & Licio Collavin

  2. Department of Life Sciences, University of Trieste, 34127, Trieste, Italy

    Daria Sicari, Marco Fantuz, Arianna Bellazzo, Elena Valentino, Mattia Apollonio, Ilaria Pontisso, Francesca Di Cristino, Marco Dal Ferro, Giannino Del Sal & Licio Collavin

  3. International School for Advanced Studies (SISSA), Trieste, Italy

    Marco Fantuz

  4. Department of Life Sciences, University of Modena and Reggio Emilia, 41100, Modena, Italy

    Silvio Bicciato

  5. IFOM, the FIRC Institute of Molecular Oncology, Trieste, Italy

    Giannino Del Sal

Authors
  1. Daria Sicari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marco Fantuz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arianna Bellazzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Elena Valentino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mattia Apollonio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ilaria Pontisso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesca Di Cristino
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marco Dal Ferro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Silvio Bicciato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giannino Del Sal
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Licio Collavin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Giannino Del Sal or Licio Collavin.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sicari, D., Fantuz, M., Bellazzo, A. et al. Mutant p53 improves cancer cells’ resistance to endoplasmic reticulum stress by sustaining activation of the UPR regulator ATF6. Oncogene 38, 6184–6195 (2019). https://doi.org/10.1038/s41388-019-0878-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0878-3

This article is cited by

Search

Advanced search

Quick links