Metabolic Reprogramming in Prostate Cancer: Impact of TP53 Gain-of-Function Mutations on Tumor Progression and Therapeutic Vulnerabilities | Chapter 12 | Achievements and Challenges of Medicine and Medical Science Vol. 13

Prostate cancer (PC) is one of the most common malignancies affecting men worldwide, and androgen hormone deprivation therapy (ADT) serves as an effective first-line treatment, inducing favorable responses in advanced PC patients. Despite advancements in the treatment of advanced prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC), the disease remains lethal, often developing resistance to conventional therapies such as androgen deprivation therapy (ADT) and chemotherapy. Therapy resistance poses a significant challenge, particularly in aggressive forms of prostate cancer. Data on TP53 mutations, especially gain-of-function (GOF) mutations, and their specific impact on prostate cancer metabolism remain limited, underscoring the need for a deeper understanding to uncover new therapeutic avenues. This study aimed to explore the metabolic consequences of TP53 GOF mutations (R175H and R273H) in prostate cancer progression using metabolomics analysis. Approximately 300 metabolites were significantly altered across PC3-GFP (KO), PC3-TP53WT (WT), and PC3-TP53 mutant (R175H & R273H) models. Key findings revealed dysregulation of essential metabolites, such as α-ketoglutarate and spermidine, which support cancer cell survival and progression. These insights not only enhance the understanding of the interplay between TP53 mutations and metabolic alterations but also identify potential biomarkers for prognosis and therapeutic targeting in therapy-resistant prostate cancer. In the TP53-R175H mutant, numerous essential metabolites were dysregulated (downregulated: glutamine, GAP/DHAP, and α-ketoglutarate; Upregulated: deoxyuridine, spermidine, and pseudouridine) when compared with the control (KO), thereby causing metabolic shifts that favor cancer cell survival. Conversely, metabolites such as GlaNAC/GlcNAC, adenosine, acetoacetic acid, acetylcholine, octopamine, itaconic acid, lactic acid, and NADP+ are all downregulated in the R273H mutant. While spermine, spermidine, N-acetyl-DL-serine, pseudouridine, deoxyguanosine, sucrose, and AMP/dGMP are upregulated by the R273H mutant but downregulated in GFP (KO). These findings showed that TP53 GOF mutations (R175H & R273H) cause metabolic alterations in numerous metabolites essential for tumor survival and progression. Furthermore, it may provide therapeutic benefits by identifying appropriate biomarkers that could be used as diagnostic and/or prognostic tools for prostate cancer. Future studies should focus on elucidating the distinct metabolic roles of each TP53 mutant, employing advanced techniques such as isotope tracing to track metabolic fluxes in real time. Additionally, therapeutic strategies targeting polyamine metabolism, redox imbalance, and TCA cycle disruptions could provide novel avenues for treatment, particularly for therapy-resistant prostate cancers.

 

Author (s) Details

Farida Jazuli Usman
Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University Kano, Nigeria.

 

Dikshat Gopal Gupta
Department of Urology and Pathology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, 60611, USA, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA and Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

 

Sarki A Abdulkadir
Department of Urology and Pathology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, 60611, USA, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA and Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

 

Ibrahim Muhammad Usman
Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University Kano, Nigeria.

 

Adamu Jibrin Alhassan
Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University Kano, Nigeria.

 

Young A Yoo
Department of Urology and Pathology, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, 60611, USA and The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

 

Haris Jaafar Bello
Department of Biochemistry, Aliko Dangote University of Science and Technology, Wudil, Kano, Nigeria.

 

Binta G. Kurfi
Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University Kano, Nigeria.

 

Kamaluddeen Babagana
Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University Kano, Nigeria.

 

Please see the book here:- https://doi.org/10.9734/bpi/acmms/v13/4559

Inhibition of Early Growth Response 1 by a Specific siRNA Modulates the Expression of p21Waf1/Cip1 and JNK-1 Proteins in Prostate PC-3 and LNCaP Carcinoma Cell Lines | Chapter 11 | Advanced Research in Biological Science Vol. 4

 This study accompanied that blocking of Egr-1 expres- sion by a limited interfering RNA (siRNA-Egr-1) raised the activity of p21Waf1/Cip1 and declined the expression of JNK protein. In contrast, siRNA muffling of p21 or JNK-1 with siRNAs was impotent to decrease the expression of Egr-1. The p21Waf1/Cip1 protein (hereafter, p21) and the c-Jun N-terminal kinase (JNK) are two well-typified cell modulators that play a critical role in container differentiation, agedness, and apoptosis. Here, we report that transcription of the p21Waf1/Cip1 and JNK-1 genes is distressed by inhibition of the early tumor response-1 (Egr-1) in reaction to a small meddling RNA [siRNA)-Egr-1] in LNCaP and PC-3 prostate carcinoma container lines. The expression levels of protein were contingent upon western blotting, and apoptosis was calculated by propidium iodide staining and flow cytometric analysis. Inhibition of Egr-1, p21 and JNK-1 was completed activity by siRNAs. LNCaP and PC-3 cells shown readily perceptible Egr-1, JNK and p21, even in low antitoxin medium without the adding of other exogenic agents. The verbalization of Egr-1, p21 and JNK was strongly raised after situation of the cells accompanying TPA, tumor fatality factor-α (TNF-α) or arsenite. Suppression of Egr-1 verbalization by siRNA abrogated the ability of TPA to encourage Egr-1 and JNK-1 activities, rather increasing the p21 endeavor and abrogating the antagonistic-apoptotic effect of Egr-1 observed in the prostate malignancy cell lines. Moreover, barrier of p21 and JNK was unable to decrease the exercise of Egr-1, while siRNA against p21 abrogated the pro-apoptotic effect of p21. The results explained that Egr-1 acts as a key player in prostate Cancer cell progress and survival, while p21 plays a key supporting-apoptotic role in LNCaP and PC-3 prostate malignant growth cell lines.

Author(s) Details:

Eduardo Parra,
Biomedical Experimental Laboratory, Faculty of Medicine, Campus Saucache, University of Tarapacá, Avenida Senador Luis Valente Rossi 2223, Arica, Chile.

Victor Rojas,
Facultad de Ciencias Agrarias y Forestales, Programa de Doctorado en Biotecnología Traslacional, Universidad Católica del Maule, Ave. San Miguel 3605, Talca, Chile.

Jorge Ferreira,
Programme of Molecular and Clinical Pharmacology, ICBM, Medical Faculty, University of Chile, Avenida Indenpendencia 1027, Independencia, Santiago, Chile.

Please see the link here: https://stm.bookpi.org/ARBS-V4/article/view/11980