Theoretical and Natural Science
- The Open Access Proceedings Series for Conferences
Theoretical and Natural Science
Vol. 16, 04 December 2023
Open
Access | Article
Review of mutant p53 protein and the p53 targeting therapy in cancer treatment
* Author to whom correspondence should be addressed.
Abstract
Cancer in humans is a disease that has been difficult to treat due to properties it is able to obtain after being introduced to an organism and has been one of the most prominent points of research in drug development. Since cancers can take on a multitude of forms, a popular strategy employed to find therapies for it is by identifying common features among cancers. A well-known alteration in half of all human cancers is TP53 mutations, of which there are more than 500. This literary review first discusses the additional capabilities cancer cells obtain, then a discussion of the various functions of p53 and the mutations it can take on. The central focus of this review will be an elucidation of the major approaches attempted in the development of cancer treatment through p53: viruses, targeting gain-of-function mutant p53, structural reactivation of mutant p53 to restore wild type activity, the depletion of mutant p53, and targeting mutant p53 through synthetic lethal inhibitors. Through exploring the different therapies, it is a universal goal to elicit one single treatment for mutant p53 that can impact the greatest amount of p53 mutations while retaining the ability to suppress or even prevent and inhibit cancer.
Keywords
Cancer, Mutant P53, Synthetic Lethal Inhibitor, Structural Reactivator, Gene Therapy
References
1. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).
2. Zuo, L. et al. Germline mutations in the p16(INK4a) binding domain of CDK4 in familial melanoma. Nat. Genet. 12, 97–99 (1996).
3. Hannon, G. J. & Beach, D. Pl5INK4B is a potentia| effector of TGF-β-induced cell cycle arrest. Nature vol. 371 257–261 (1994).
4. Datto, M. B., Hu, P. P.-C., Kowalik, T. F., Yingling, J. & Wang, X.-F. The Viral Oncoprotein E1A Blocks Transforming Growth Factor β-Mediated Induction of p21/WAF1/Cip1 and p15/INK4B. Mol. Cell. Biol. 17, 2030–2037 (1997).
5. Foley, K. P. & Eisenman, R. N. Two MAD tails: What the recent knockouts of Mad1 and Mxi1 tell us about the MYC/MAX/MAD network. Biochim. Biophys. Acta - Rev. Cancer 1423, 37–47 (1999).
6. Wright, W. E., Pereira-Smith, O. M. & Shay, J. W. Reversible Cellular Senescence: Implications for Immortalization of Normal Human Diploid Fibroblasts. Mol. Cell. Biol. 9, 3088–3092 (1989).
7. Bischoff, C. et al. No association between telomere length and survival among the elderly and oldest old. Epidemiology 17, 190–194 (2006).
8. Counter, C. M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 (1992).
9. Bryan, T. M., Englezou, A., Gupta, J., Bacchetti, S. & Reddel, R. R. Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J. 14, 4240–4248 (1995).
10. Bouck, N., Stellmach, V. & Hsu, S. C. How tumors become angiogenic. Adv. Cancer Res. 69, 135–174 (1996).
11. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
12. Veikkola, T. & U, K. A. Veikkola1999. 9, (1999).
13. DeLeo, A. B. et al. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc. Natl. Acad. Sci. U. S. A. 76, 2420–2424 (1979).
14. Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SY40-transformed cells [19]. Nature 278, 261–263 (1979).
15. Kress, M., May, E., Cassingena, R. & May, P. Simian virus 40-transformed cells express new species of proteins precipitable by anti-simian virus 40 tumor serum. J. Virol. 31, 472–483 (1979).
16. Eliyahu, D., Michalovitz, D., Eliyahu, S., Pinhasi-Kimhi, O. & Oren, M. Wild-type p53 can inhibit oncogene-mediated focus formation. Proc. Natl. Acad. Sci. U. S. A. 86, 8763–8767 (1989).
17. Finlay, C. A., Hinds, P. W. & Levine, A. J. The p53 proto-oncogene can act as a suppressor of transformation. Cell 57, 1083–1093 (1989).
18. Maltzman, W. & Czyzyk, L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell. Biol. 4, 1689–1694 (1984).
19. Bouaoun, L. et al. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data. Hum. Mutat. 37, 865–876 (2016).
20. Zhu, J., Dou, Z., Sammons, M. A., Levine, A. J. & Berger, S. L. Lysine methylation represses P53 activity in teratocarcinoma cancer cells. Proc. Natl. Acad. Sci. U. S. A. 113, 9822–9827 (2016).
21. Levine, A. J. The p53 protein plays a central role in the mechanism of action of epigentic drugs that alter the methylation of cytosine residues in DNA. Oncotarget 8, 7228–7230 (2017).
22. Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551, S12–S16 (2017).
23. Levine, A. J. Targeting Therapies for the p53 Protein in Cancer Treatments. Annu. Rev. Cancer Biol. 3, 21–34 (2019).
24. Dittmer, D. et al. Gain of function mutations in p53. Nat. Genet. 4, 42–46 (1993).
25. Wu, X., Bayle, J. H., Olson, D. & Levine, A. J. The p53-mdm-2 autoregulatory feedl ack loop. 53, 1126–1132 (1993).
26. Karlseder, J., Broccoli, D. & Dai, Y. Apoptosis Induced by Telomeres Lacking TRFZ. Science (80-. ). 283, 0–4 (1999).
27. Bykov, V. J. N. et al. Inhibition of tumor angiogenesis by p53: A new role for the guardian of the genome. Cell 4, 1761–1761 (2010).
28. Sermeus, A. & Michiels, C. Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis. 2, e164-11 (2011).
29. Zhang, Y. & Lu, H. Signaling to p53: Ribosomal Proteins Find Their Way. Cancer Cell 16, 369–377 (2009).
30. Vogel, C., Kienitz, A., Hofmann, I., Müller, R. & Bastians, H. Crosstalk of the mitotic spindle assembly checkpoint with p53 to prevent polyploidy. Oncogene 23, 6845–6853 (2004).
31. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16(INK4a). Cell 88, 593–602 (1997).
32. Fridman, J. S. & Lowe, S. W. Control of apoptosis by p53. Oncogene 22, 9030–9040 (2003).
33. Maiuri, M. C. et al. Autophagy regulation by p53. Curr. Opin. Cell Biol. 22, 181–185 (2010).
34. Smith, M. L. & Seo, Y. R. p53 regulation of DNA excision repair pathways. Mutagenesis 17, 149–156 (2002).
35. Demidenko, Z. N., Korotchkina, L. G., Gudkov, A. V. & Blagosklonny, M. V. Paradoxical suppression of cellular senescence by p53. Proc. Natl. Acad. Sci. U. S. A. 107, 9660–9664 (2010).
36. Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).
37. Stuart G.Lutzker and Arnold Levine. A functionally inactive p53 protein interatocarcinoma cells is activated by either DNA damage or cellular differentiation. 2, 601–603 (1996).
38. Waldman, T., Kinzler, K. W. & Vogelstein, B. p21 Is Necessary for the p53-mediated G1 Arrest in Human Cancer Cells. Cancer Res. 55, 5187–5190 (1995).
39. Jin, S. et al. GADD45-induced cell cycle G2-M arrest associates with altered subcellular distribution of cyclin B1 and is independent of p38 kinase activity. Oncogene 21, 8696–8704 (2002).
40. Levine, A. J. & Puzio-Kuter, A. M. The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science (80-. ). 330, 1340–1344 (2010).
41. Teodoro, J. G., Evans, S. K. & Green, M. R. Inhibition of tumor angiogenesis by p53: A new role for the guardian of the genome. J. Mol. Med. 85, 1175–1186 (2007).
42. Menendez, D., Shatz, M. & Resnick, M. A. Interactions between the tumor suppressor p53 and immune responses. Curr. Opin. Oncol. 25, 85–92 (2013).
43. Levine, A. J. The many faces of p53: Something for everyone. J. Mol. Cell Biol. 11, 524–530 (2019).
44. Sarnow, P., Ho, Y. S., Williams, J. & Levine, A. J. Adenovirus E1b-58kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell 28, 387–394 (1982).
45. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).
46. Heise, C. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature 3, 639–645 (1997).
47. Peng, X. et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 4, 1–7 (2013).
48. Martinez, L. A. et al. Synthetic small inhibiting RNAs: Efficient tools to inactivate oncogenic mutations and restore p53 pathways. Proc. Natl. Acad. Sci. U. S. A. 99, 14849–14854 (2002).
49. Hinds, P. W., Finlay, C. A., Frey, A. B. & Levine, A. J. Immunological Evidence for the Association of P53 with a Heat Shock Protein, hsc70, in p53-plus- ras -Transformed Cell Lines . Mol. Cell. Biol. 7, 2863–2869 (1987).
50. Freed-Pastor, W. A. et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell 148, 244–258 (2012).
51. Duffy, M. J., Synnott, N. C. & Crown, J. p53 in cancer: Ready for therapeutic targeting? Transl. Cancer Res. 5, 627–631 (2016).
52. Kogan, S. & Carpizo, D. Pharmacological targeting of mutant p53. Transl. Cancer Res. 5, 698–706 (2016).
53. Sabapathy, K. & Lane, D. P. Therapeutic targeting of p53: All mutants are equal, but some mutants are more equal than others. Nat. Rev. Clin. Oncol. 15, 13–30 (2018).
54. Foster, B. A. et al. Pharmacological Rescue of Mutant p53 Conformation and Function Published by : American Association for the Advancement of Science Stable URL : https://www.jstor.org/stable/2899883 Linked references are available on JSTOR for this article : digitize , pres. 286, 2507–2510 (2019).
55. Joerger, A. C., Ang, H. C. & Fersht, A. R. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc. Natl. Acad. Sci. U. S. A. 103, 15056–15061 (2006).
56. Bromley, D., Bauer, M. R., Fersht, A. R. & Daggett, V. An in silico algorithm for identifying stabilizing pockets in proteins: Test case, the Y220C mutant of the p53 tumor suppressor protein. Protein Eng. Des. Sel. 29, 377–390 (2016).
57. Qian, M. X. et al. XAcetylation-mediated proteasomal degradation of core histones during DNA repair and spermatogenesis. Cell 153, 1012 (2013).
58. Park, E. Y. et al. Targeting of miR34a-NOTCH1 axis reduced breast cancer stemness and chemoresistance. Cancer Res. 74, 7573–7582 (2014).
59. Blanden, R. et al. Erratum: Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore (Molecular Pharmacology (2015) 87 (825-831)). Mol. Pharmacol. 88, 1084 (2015).
60. Verhaegh, G. W., Parat, M. O., Richard, M. J. & Hainaut, P. Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc. Mol. Carcinog. 21, 205–214 (1998).
61. Lambert, J. M. R. et al. PRIMA-1 Reactivates Mutant p53 by Covalent Binding to the Core Domain. Cancer Cell 15, 376–388 (2009).
62. Zhang, Q., Bykov, V. J. N., Wiman, K. G. & Zawacka-Pankau, J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 9, (2018).
63. Bykov, V. J. N. & Wiman, K. G. Mutant p53 reactivation by small molecules makes its way to the clinic. FEBS Lett. 588, 2622–2627 (2014).
64. Hu, J. et al. Targeting mutant p53 for cancer therapy: direct and indirect strategies. J. Hematol. Oncol. 14, 1–19 (2021).
65. Friedler, A. et al. Chaperone strategy for rescue of oncogenic mutants Il. (2018).
66. Nikolova, P. V., Wong, K. B., DeDecker, B., Henckel, J. & Fersht, A. R. Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations. EMBO J. 19, 370–378 (2000).
67. Schulz-Heddergott, R. & Moll, U. M. Gain-of-function (GOF) mutant p53 as actionable therapeutic target. Cancers (Basel). 10, 1–16 (2018).
68. Subramanian, M. et al. A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis. Oncogene 34, 1094–1104 (2015).
69. Li, D., Marchenko, N. D. & Moll, U. M. SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis. Cell Death Differ. 18, 1904–1913 (2011).
70. Lin, K., Rockliffe, N., Johnson, G. G., Sherrington, P. D. & Pettitt, A. R. Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells. Oncogene 27, 2445–2455 (2008).
71. Qiu, Z., Oleinick, N. L. & Zhang, J. ATR/CHK1 inhibitors and cancer therapy. Radiother. Oncol. 126, 450–464 (2018).
72. Cimprich, K. A. & Cortez, D. ATR: An essential regulator of genome integrity. Nat. Rev. Mol. Cell Biol. 9, 616–627 (2008).
73. Konstantinopoulos, P. A. et al. Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 21, 957–968 (2020).
74. Fang, B. Development of synthetic lethality anticancer therapeutics. J. Med. Chem. 57, 7859–7873 (2014).
75. Reinhardt, H. C., Aslanian, A. S., Lees, J. A. & Yaffe, M. B. p53-Deficient Cells Rely on ATM- and ATR-Mediated Checkpoint Signaling through the p38MAPK/MK2 Pathway for Survival after DNA Damage. Cancer Cell 11, 175–189 (2007).
76. Song, J., Yu, J., Jeong, L. S. & Lee, S. K. A Novel cytarabine analog evokes synthetic lethality by targeting MK2 in p53-deficient cancer cells. Cancer Lett. 497, 54–65 (2021).
77. Vousden, K. H. & Ryan, K. M. P53 and metabolism. Nat. Rev. Cancer 9, 691–700 (2009).
78. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: The next generation. Cell 144, 646–674 (2011).
79. Zhang, C. et al. Tumour-associated mutant p53 drives the Warburg effect. Nat. Commun. 4, (2013).
80. Mathupala, S. P., Heese, C. & Pedersen, P. L. Glucose catabolism in cancer cells. The type II hexokinase promoter contains functionally active response elements for the tumor suppressor p53. J. Biol. Chem. 272, 22776–22780 (1997).
81. Wang, L. et al. Hexokinase 2-Mediated Warburg Effect Is Required for PTEN- and p53-Deficiency-Driven Prostate Cancer Growth. Cell Rep. 8, 1461–1474 (2014).
82. D’Orazi, G. & Cirone, M. Mutant p53 and cellular stress pathways: A criminal alliance that promotes cancer progression. Cancers (Basel). 11, (2019).
83. Shi, Y., Norberg, E. & Vakifahmetoglu-Norberg, H. Mutant p53 as a Regulator and Target of Autophagy. Front. Oncol. 10, (2021).
84. Sargolzaei, J., Etemadi, T. & Alyasin, A. The P53/microRNA network: A potential tumor suppressor with a role in anticancer therapy. Pharmacol. Res. 160, 105179 (2020).
85. Bushati, N. & Cohen, S. M. MicroRNA functions. Annu. Rev. Cell Dev. Biol. 23, 175–205 (2007).
86. Krell, J. et al. The p53 miRNA interactome and its potential role in the cancer clinic. Epigenomics 5, 417–428 (2013).
87. Ju, Q. et al. Mutant p53 increases exosome-mediated transfer of miR-21-3p and miR-769-3p to promote pulmonary metastasis. Chinese J. Cancer Res. 31, 533–546 (2019).
88. Tarasov, V., Jung, P., Verdoodt, B., Epanchintsev, A. & Hermeking, H. Differential Regulation of microRNAs by p53 ND ES SC RIB. Cell Cycle 1586–1593 (2007).
89. Jiang, L. & Hermeking, H. MiR-34a and miR-34b/c suppress intestinal tumorigenesis. Cancer Research vol. 77 (2017).
90. Hong, D. S. et al. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. Br. J. Cancer 122, 1630–1637 (2020).
91. Masciarelli, S. et al. Gain-of-function mutant p53 downregulates miR-223 contributing to chemoresistance of cultured tumor cells. Oncogene 33, 1601–1608 (2014).
92. Luo, P. et al. MiR-223-3p functions as a tumor suppressor in lung squamous cell carcinoma by miR-223-3p-mutant p53 regulatory feedback loop. J. Exp. Clin. Cancer Res. 38, 1–12 (2019).
93. Capaci, V. et al. Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome. Nat. Commun. 11, 1–19 (2020).
94. Dhanoa, J. K., Sethi, R. S., Verma, R., Arora, J. S. & Mukhopadhyay, C. S. Long non-coding RNA: Its evolutionary relics and biological implications in mammals: A review. J. Anim. Sci. Technol. 60, 1–10 (2018).
95. Blume, C. J. et al. P53-dependent non-coding RNA networks in chronic lymphocytic leukemia. Leukemia 29, 2015–2023 (2015).
96. Jin, S. et al. P53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma. Mol. Cancer 18, 1–18 (2019).
97. Kristensen, L. S. et al. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20, 675–691 (2019).
98. Fang, L. et al. Enhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1. Cell Death Differ. 25, 2195–2208 (2018).
Data Availability
The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.
This work is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License. Authors who publish this series agree to the following terms:
1. Authors retain copyright and grant the series right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this series.
2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the series's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this series.
3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See Open Access Instruction).
- Volume Title
- Proceedings of the 2nd International Conference on Modern Medicine and Global Health
- ISBN (Print)
- 978-1-83558-195-7
- ISBN (Online)
- 978-1-83558-196-4
- Published Date
- 04 December 2023
- Series
- Theoretical and Natural Science
- ISSN (Print)
- 2753-8818
- ISSN (Online)
- 2753-8826
- DOI
- 10.54254/2753-8818/16/20240550
- Copyright
- 04 December 2023
- Open Access
- This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited