Review
Oncology
Yen-Ting Chiang, Yi-Chung Chien, Yu-Heng Lin, Hui-Hsuan Wu, Dung-Fang Lee, Yung-Luen Yu
Summary: TP53 is a well-known tumor-suppressor gene commonly mutated in cancer, with missense mutations occurring at hotspots like p53-R175H, promoting cancer progression. Mutant p53 proteins lose wild-type functions and gain oncogenic functions, leading to enhanced proliferation, migration, invasion, and drug resistance in cancer cells. Research focuses on understanding the gain of function of p53-R175H in different cancer types and developing treatments targeting this mutation, such as small molecules to reactivate or degrade p53-R175H and immunotherapies targeting the p53-R175H-HLA complex.
Review
Biochemistry & Molecular Biology
Shengliang Zhang, Lindsey Carlsen, Liz Hernandez Borrero, Attila A. Seyhan, Xiaobing Tian, Wafik S. El-Deiry
Summary: This article summarizes the current progress in targeting wild-type and mutant p53 for cancer therapy using biotherapeutic and biopharmaceutical methods. Strategies include boosting p53 activity, restoring p53 pathway function, targeting p53 in immunotherapy, and combination therapies.
Review
Pharmacology & Pharmacy
Jiajian Wang, Wenjun Liu, Lanqing Zhang, Jihong Zhang
Summary: More than 50% of cancer patients have TP53 mutation, and the highly stabilized mutant p53 protein plays a crucial role in tumorigenesis and progression. The mutation of p53 not only leads to loss-of-function and dominant-negative effects, but also promotes tumorigenesis through abnormal stability regulated by the ubiquitin-proteasome system and molecular chaperones. The accumulation of mutant p53 is mainly controlled by molecular chaperones, such as Hsp40, Hsp70, Hsp90, as well as other biomolecules like TRIM21, BAG2, and Stat3. Additionally, mutant p53 can form prion-like aggregates or complexes with other proteins, leading to its accumulation in tumor cells. Depleting mutant p53 has become a strategy for targeting mutant p53, and this review focuses on the mechanisms of mutant p53 stabilization and discusses strategies to manipulate these interconnected processes for cancer therapy.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Oncology
Kate Brown, Lisa M. Miller Jenkins, Daniel R. Crooks, Deborah R. Surman, Sharlyn J. Mazur, Yuan Xu, Bhargav S. Arimilli, Ye Yang, Andrew N. Lane, Teresa W-M. Fan, David S. Schrump, W. Marston Linehan, R. Taylor Ripley, Ettore Appella
Summary: TP53 is the most frequently mutated gene in cancer, with various gain-of-function mutations. The NSC59984 compound has been found to reactivate mutant p53 in colorectal cancer cells. This study investigated the effects of NSC59984 on esophageal adenocarcinoma cells with specific p53 hot-spot mutations and demonstrated its p53-dependent effects on cellular metabolism, with greater activity in cells harboring the p53 R248W mutation.
FRONTIERS IN ONCOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Katarzyna A. Roszkowska, Aleksandra Piecuch, Maria Sady, Zdzislaw Gajewski, Sylwia Flis
Summary: This review focuses on several novel therapeutic opportunities, including APR-246, COTI-2, SAHA, and PEITC, which can reactivate p53 or destabilize mutant p53, and discusses their significance for potential medical application.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Qiaosi Tang, Gizem Efe, Anna M. Chiarella, Jessica Leung, Maoting Chen, Taiji Yamazoe, Zhenyi Su, Jason R. Pitarresi, Jinyang Li, Mirazul Islam, Tatiana Karakasheva, Andres J. Klein-Szanto, Samuel Pan, Jianhua Hu, Shoji Natsugoe, Wei Gu, Ben Z. Stanger, Kwok-K Wong, J. Alan Diehl, Adam J. Bass, Hiroshi Nakagawa, Maureen E. Murphy, Anil K. Rustgi
Summary: Esophageal squamous cell carcinoma (ESCC) is a deadly cancer that often metastasizes to the lungs. The study investigated how the p53R175H mutation regulates metastasis in ESCC. Depletion of Trp53R172H in primary tumor cell lines led to reduced invasion and lung metastasis, with the YAP-BIRC5 axis identified as a potential mediator. Survivin, a protein encoded by BIRC5, was found to be upregulated by Trp53R172H and associated with increased metastasis in GI cancers. These findings provide new insights into mutant p53-mediated metastasis.
GENES & DEVELOPMENT
(2021)
Article
Biology
Mengchen Zhou, Yan Yao, Xiangyi Wang, Lingfeng Zha, Yilin Chen, Yanze Li, Mengru Wang, Chenguang Yu, Yingchao Zhou, Qianqian Li, Zhubing Cao, Jianfei Wu, Shumei Shi, Dan Jiang, Deyong Long, Jiangang Wang, Qing Wang, Xiang Cheng, Yuhua Liao, Xin Tu
Summary: Six variations of KIF1C leading to decreased expression levels are found in patients with left atrial myxoma (LAM). Inhibition of KIF1C promotes LAM pathogenesis through a positive feedback formed by the crosstalk between KIF1C and PRKAR1A.
COMMUNICATIONS BIOLOGY
(2023)
Review
Oncology
Jiahao Hu, Jiasheng Cao, Win Topatana, Sarun Juengpanich, Shijie Li, Bin Zhang, Jiliang Shen, Liuxin Cai, Xiujun Cai, Mingyu Chen
Summary: TP53 is a critical tumor-suppressor gene commonly mutated in human cancers, with potential oncogenic properties when mutated. Treatments for cancers with mutant p53 involve targeting mutant p53 directly, restoring wild-type functions, and exploring synthetic lethal interactions with mutant p53 for therapeutic benefits. Additionally, disrupting noncoding RNA networks may have potential synthetic lethal effects in cancers with p53 mutations.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Cell Biology
Laura Mainz, Mohamed A. F. E. Sarhan, Sabine Roth, Ursula Sauer, Katja Maurus, Elena M. Hartmann, Helen-Desiree Seibert, Andreas Rosenwald, Markus E. Diefenbacher, Mathias T. Rosenfeldt
Summary: Autophagy is a homeostatic process that regulates the development of pancreatic ductal adenocarcinoma (PDAC). In a genetically engineered mouse model, we found that blocking autophagy reduced the incidence of PDAC, but did not affect the survival time of animals with tumors. Additionally, the absence of autophagy led to changes in the structure of the pancreas and a decrease in the number of insulin-expressing cells.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Mehregan Babamohamadi, Esmaeil Babaei, Burhan Ahmed Salih, Mahshid Babamohammadi, Hewa Jalal Azeez, Goran Othman
Summary: The p53 protein is a tumor suppressor that regulates various cellular processes and is closely related to cancer development. It can be used as a biomarker for tumor progression and a target for cancer treatment. This review discusses the contribution of wild-type p53 loss of function, its role in ferroptosis and targeted therapy, and challenges and solutions in p53-related drug delivery systems.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Pharmacology & Pharmacy
Lulu Guan, Yalan Yang, Yao Lu, Yu Chen, Xi Luo, Dao Xin, Xiangrui Meng, Zhengzheng Shan, Guozhong Jiang, Feng Wang
Summary: p53 mutations are common in human cancers, especially esophageal cancer. The mutant p53 protein promotes cancer progression and drug resistance. This study investigated the antitumor effects of PEITC in esophageal squamous cell carcinoma (ESCC) with p53 mutations and found that PEITC can restore p53 activity, inhibit the growth of ESCC, induce apoptosis, and arrest cell cycle progression. Mechanistic studies revealed that PEITC restores the wild-type conformation and transactivation function of p53. These findings suggest that PEITC has potential as a therapeutic strategy for p53-mutant ESCC.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Cell Biology
Steven Pilley, Tristan A. Rodriguez, Karen H. Vousden
Summary: p53 is a crucial tumor suppressor gene, and mutations in p53 can impact cancer development and progression. In addition to its cell-autonomous functions, the status of p53 can also influence the interactions between cancer cells.
GENES & DEVELOPMENT
(2021)
Review
Biochemistry & Molecular Biology
Oleg Semenov, Alexandra Daks, Olga Fedorova, Oleg Shuvalov, Nickolai A. Barlev
Summary: The aberrantly activated EMT program plays a central role in defining the critical features of aggressive carcinomas, and the p53 gene is critical for suppressing these features. Specific mutations in the p53 gene can convert it into an oncogene. This review contrasts the different regulatory roles of wild-type and mutant p53 in the process of EMT.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Cell Biology
Takatsune Shimizu, Eiji Sugihara, Hideyuki Takeshima, Hiroyuki Nobusue, Rui Yamaguchi, Sayaka Yamaguchi-Iwai, Yumi Fukuchi, Toshikazu Ushijima, Akihiro Muto, Hideyuki Saya
Summary: Mutant p53 in osteosarcoma cells does not suppress the activity of wild-type p53. Targeting mutant p53 R270C (equivalent to human R273C) has limited therapeutic potential, as it does not prevent invasion and metastasis in cells.
Article
Biochemistry & Molecular Biology
Julie Xia Zhou, Ewud Agborbesong, Linda Xiaoyan Li, Xiaogang Li
Summary: This study reveals a novel regulatory mechanism of mutant p53 through BRD4 in triple-negative breast cancer (TNBC). Inhibition of BRD4 reduces the transcription of mutant p53 and suppresses the tumorigenesis of TNBC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
