PBA Preferentially Impairs Cell Survival of Glioblastomas Carrying Mutp53 by Reducing Its Expression Level, Stabilizing Wtp53, Downregulating the Mevalonate Kinase and Dysregulating UPR

Overview

Journal Biomolecules

Publisher MDPI

Specialties Biochemistry
Molecular Biology

Date 2020 Apr 16

PMID 32290231

Citations 4

Authors

Maria Anele Romeo

Maria Saveria Gilardini Montani

Rossella Benedetti

Alessia Garufi

Gabriella DOrazi

Mara Cirone

Affiliations

Soon will be listed here.

Abstract

Phenylbutyrate (PBA) is a derivative of Butyric Acid (BA), which has the characteristics of being a histone deacetylase (HDAC) inhibitor and acting as a chemical chaperone. It has the potential to counteract a variety of different diseases, from neurodegeneration to cancer. In this study, we investigated the cytotoxic effect of PBA against glioblastoma cells carrying wt or mutant (mut) p53 and found that it exerted a higher cytotoxic effect against the latter in comparison with the former. This could be due to the downregulation of mutp53, to whose pro-survival effects cancer cells become addicted. In correlation with mutp53 reduction and wtp53 activation, PBA downregulated the expression level of mevalonate kinase (MVK), a key kinase of the mevalonate pathway strongly involved in cancer cell survival. Here we differentiated the chaperoning function of PBA from the others anti-cancer potentiality by comparing its effects to those exerted by NaB, another HDACi that derives from BA but, lacking the phenyl group, cannot act as a chemical chaperone. Interestingly, we observed that PBA induced a stronger cytotoxic effect compared to NaB against U373 cells as it skewed the Unfolded Protein Response (UPR) towards cell death induction, upregulating CHOP and downregulating BIP, and was more efficient in downregulating MVK. The findings of this study suggest that PBA represents a promising molecule against glioblastomas, especially those carrying mutp53, and its use, approved by FDA for urea cycle disorders, should be extended to the glioblastoma anticancer therapy.

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References

Moon S, Huang C, Houlihan S, Regunath K, Freed-Pastor W, Morris 4th J . p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. Cell. 2018; 176(3):564-580.e19. PMC: 6483089. DOI: 10.1016/j.cell.2018.11.011. View

Gilardini Montani M, Cecere N, Granato M, Romeo M, Falcinelli L, Ciciarelli U . Mutant p53, Stabilized by Its Interplay with HSP90, Activates a Positive Feed-Back Loop Between NRF2 and p62 that Induces Chemo-Resistance to Apigenin in Pancreatic Cancer Cells. Cancers (Basel). 2019; 11(5). PMC: 6562395. DOI: 10.3390/cancers11050703. View

Wang Z, Wu Y, Wang H, Zhang Y, Mei L, Fang X . Interplay of mevalonate and Hippo pathways regulates RHAMM transcription via YAP to modulate breast cancer cell motility. Proc Natl Acad Sci U S A. 2013; 111(1):E89-98. PMC: 3890879. DOI: 10.1073/pnas.1319190110. View

Samid D, Ram Z, Hudgins W, Shack S, Liu L, Walbridge S . Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. Cancer Res. 1994; 54(4):891-5. View

Pirmoradi L, Seyfizadeh N, Ghavami S, Zeki A, Shojaei S . Targeting cholesterol metabolism in glioblastoma: a new therapeutic approach in cancer therapy. J Investig Med. 2019; 67(4):715-719. DOI: 10.1136/jim-2018-000962. View

Ingallina E, Sorrentino G, Bertolio R, Lisek K, Zannini A, Azzolin L . Mechanical cues control mutant p53 stability through a mevalonate-RhoA axis. Nat Cell Biol. 2017; 20(1):28-35. PMC: 6179142. DOI: 10.1038/s41556-017-0009-8. View

Kusaczuk M, Bartoszewicz M, Cechowska-Pasko M . Phenylbutyric Acid: simple structure - multiple effects. Curr Pharm Des. 2015; 21(16):2147-66. DOI: 10.2174/1381612821666150105160059. View

Avril T, Vauleon E, Chevet E . Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers. Oncogenesis. 2017; 6(8):e373. PMC: 5608920. DOI: 10.1038/oncsis.2017.72. View

Friedler A, Hansson L, Veprintsev D, Freund S, Rippin T, Nikolova P . A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc Natl Acad Sci U S A. 2002; 99(2):937-42. PMC: 117409. DOI: 10.1073/pnas.241629998. View

10.

Ryu H, Shin D, Lee D, Choi J, Han G, Lee K . HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis. Cancer Lett. 2017; 391:162-171. DOI: 10.1016/j.canlet.2017.01.033. View

11.

Kusaczuk M, Kretowski R, Bartoszewicz M, Cechowska-Pasko M . Phenylbutyrate-a pan-HDAC inhibitor-suppresses proliferation of glioblastoma LN-229 cell line. Tumour Biol. 2015; 37(1):931-42. PMC: 4841856. DOI: 10.1007/s13277-015-3781-8. View

12.

Parrales A, Ranjan A, Iyer S, Padhye S, Weir S, Roy A . DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway. Nat Cell Biol. 2016; 18(11):1233-1243. PMC: 5340314. DOI: 10.1038/ncb3427. View

13.

Damaskos C, Garmpis N, Valsami S, Kontos M, Spartalis E, Kalampokas T . Histone Deacetylase Inhibitors: An Attractive Therapeutic Strategy Against Breast Cancer. Anticancer Res. 2016; 37(1):35-46. DOI: 10.21873/anticanres.11286. View

14.

Freed-Pastor W, Mizuno H, Zhao X, Langerod A, Moon S, Rodriguez-Barrueco R . Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012; 148(1-2):244-58. PMC: 3511889. DOI: 10.1016/j.cell.2011.12.017. View

15.

DOrazi G, Cirone M . Mutant p53 and Cellular Stress Pathways: A Criminal Alliance That Promotes Cancer Progression. Cancers (Basel). 2019; 11(5). PMC: 6563084. DOI: 10.3390/cancers11050614. View

16.

Martin G, Duez H, Blanquart C, Berezowski V, Poulain P, Fruchart J . Statin-induced inhibition of the Rho-signaling pathway activates PPARalpha and induces HDL apoA-I. J Clin Invest. 2001; 107(11):1423-32. PMC: 209316. DOI: 10.1172/JCI10852. View

17.

Bathaie S, Ashrafi M, Azizian M, Tamanoi F . Mevalonate Pathway and Human Cancers. Curr Mol Pharmacol. 2016; 10(2):77-85. DOI: 10.2174/1874467209666160112123205. View

18.

Suva M, Riggi N, Bernstein B . Epigenetic reprogramming in cancer. Science. 2013; 339(6127):1567-70. PMC: 3821556. DOI: 10.1126/science.1230184. View

19.

Gilardini Montani M, Granato M, Santoni C, Del Porto P, Merendino N, DOrazi G . Histone deacetylase inhibitors VPA and TSA induce apoptosis and autophagy in pancreatic cancer cells. Cell Oncol (Dordr). 2017; 40(2):167-180. DOI: 10.1007/s13402-017-0314-z. View

20.

Hsu S, Chiu C, Dahms H, Chou C, Cheng C, Chang W . Unfolded Protein Response (UPR) in Survival, Dormancy, Immunosuppression, Metastasis, and Treatments of Cancer Cells. Int J Mol Sci. 2019; 20(10). PMC: 6566956. DOI: 10.3390/ijms20102518. View