Evaluation of the Role of p53 Tumour Suppressor Posttranslational Modifications and TTC5 Cofactor in Lung Cancer

Abstract

Mutations in the p53 tumor suppressor are found in over 50% of cancers. p53 function is controlled through posttranslational modifications and cofactor interactions. In this study, we investigated the posttranslationally modified p53, including p53 acetylated at lysine 382 (K382), p53 phosphorylated at serine 46 (S46), and the p53 cofactor TTC5/STRAP (Tetratricopeptide repeat domain 5/ Stress-responsive activator of p300-TTC5) proteins in lung cancer. Immunohistochemical (IHC) analysis of lung cancer tissues from 250 patients was carried out and the results were correlated with clinicopathological features. Significant associations between total or modified p53 with a higher grade of the tumour and shorter overall survival (OS) probability were detected, suggesting that mutant and/or modified p53 acts as an oncoprotein in these patients. Acetylated at K382 p53 was predominantly nuclear in some samples and cytoplasmic in others. The localization of the K382 acetylated p53 was significantly associated with the gender and grade of the disease. The TTC5 protein levels were significantly associated with the grade, tumor size, and node involvement in a complex manner. SIRT1 expression was evaluated in 50 lung cancer patients and significant positive correlation was found with p53 S46 intensity, whereas negative TTC5 staining was associated with SIRT1 expression. Furthermore, p53 protein levels showed positive association with poor OS, whereas TTC5 protein levels showed positive association with better OS outcome. Overall, our results indicate that an analysis of p53 modified versions together with TTC5 expression, upon testing on a larger sample size of patients, could serve as useful prognostic factors or drug targets for lung cancer treatment.

Mitochondria: It is all about energy

“…HIF1 overexpression, oncogene activation (cMyc, K-ras- mTORC1, and Akt), activation of signaling pathways (PI3K/Akt/mTORC1, Ras/Raf/MEK/ERK), an increase in glucose (GLUT) and lactate (MCT4) transporters, and the activation of glycolytic enzymes (HK2, PFK1, ENO1, PKM2, and LDHA) ( Wallace, 2005 ; Choudhury et al, 2020 ; Han et al, 2021 ; Mariani et al, 2021 ; Pluimakers et al, 2021 ; Shen et al, 2021 ; Vaupel and Multhoff, 2021 ; Zhu et al, 2022c ) are all part of the metabolic change observed in cancer cells. Furthermore, the functions of tumor suppressors (mutant p53, mutant PTEN, and microRNAs 29, 143, and 144), Sirtuins 3 and 6, and the AMPK signaling pathway ( Kumar et al, 2016 ; Alhebshi et al, 2021 ; Jazvinšćak Jembrek et al, 2021 ; Zhang et al, 2022a ) are inhibited to prevent cell death and reduce metabolic stress of tumor cells. The metabolic changes belonging to the Warburg effect can be influenced by the known physiological hormetic triggers that could serve as primary and perhaps secondary preventive interventions ( Jazvinšćak Jembrek et al, 2021 ).…”

Targeting the p53 signaling pathway in cancers: Molecular mechanisms and clinical studies

“…Malignant melanoma and HCC patients with high levels of p53 Lys373 acetylation have relatively longer OS and early, lower lymph node metastasis 98,99 . HCC, malignant melanoma, and lung cancer patients with high levels of p53 Lys382 acetylation have relatively longer OS and earlier stage and lower lymph node metastasis 98–100 …”

“… 98 , 99 HCC, malignant melanoma, and lung cancer patients with high levels of p53 Lys382 acetylation have relatively longer OS and earlier stage and lower lymph node metastasis. 98 , 99 , 100 …”