Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles

Antoun, Stephanie; Atallah, David; Tahtouh, Roula; Alaaeddine, Nada; Moubarak, Malak; Khaddage, Abir; Ayoub, Eliane; Chahine, G.; Hilal, George

doi:10.1186/s12935-018-0514-2

Cited by 13 publications

(10 citation statements)

References 30 publications

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“…p53 is an important target protein for SIRT1.Previous study indicated that the selective SIRT1 inhibitor, EX527, significantly suppressed the proliferation of endometrial carcinoma cells regardless of the p53 mutation status [52,53]. Thus, activation of the p53 pathway through SIRT1 inhibition has been shown to have powerful anticancer effects [54]. Our present data indicate that activation of the apoptosis-related signal pathway via up-regulation of p53, plays a pivotal role in MHY2245-induced cell death.…”

Section: Discussionsupporting

confidence: 51%

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Tae¹,

Son²,

Lee³

et al. 2020

Int. J. Biol. Sci.

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Ovarian cancer is a common gynecological cancer that is found worldwide. Class III histone deacetylase (HDAC) inhibitors, a new class of anticancer agents, induce autophagy in various human cancer cells. The aim of the present study was to investigate the antitumor activity of MHY2245, a new synthetic SIRT inhibitor, on human ovarian cancer cells. We found that MHY2245 exhibited potent cytotoxicity to SKOV3 cells in a time-and concentration-dependent manner. The cytotoxicity of MHY2245 (IC 50 =0.32 µM) was higher than that of doxorubicin (DOX, IC 50 =1.38µM) against SKOV3 cells. MHY2245 significantly inhibited SIRT1 enzyme activity, reduced the expression of SIRT1, increased cell cycle arrest at G 2 /M phase, and induced apoptotic cell death in SKOV3 cells via expression of cytochrome c, cleaved-PARP, cleaved caspase-3, and Bax. This might be associated with blocking of the pyruvate kinase M2 (PKM2)/mTOR pathway. MHY2245 also inhibited tumor growth and reduced tumor size when SKOV3 cells were transplanted into nude mice. Our results indicate that MHY2245 exerts antitumor activity against ovarian cancer cells by blocking the PKM2/mTOR pathway. We suggest that MHY2245 is a promising anticancer agent that disrupts ovarian cancer cell metabolism.

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Section: Discussionsupporting

confidence: 51%

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

Tae¹,

Son²,

Lee³

et al. 2020

Int. J. Biol. Sci.

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“…However, one particular mutation p53P72R showed increased PGC1α function and increased metastatic capability [ 191 ]. Even though this mutation didn't show evidence of increased glucose regulation compared to wild-type p53 [ 192 ].…”

Section: Regulation Of Metabolism By P53mentioning

confidence: 99%

p53 and metabolism: from mechanism to therapeutics

et al. 2018

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The tumor cell changes itself and its microenvironment to adapt to different situations, including action of drugs and other agents targeting tumor control. Therefore, metabolism plays an important role in the activation of survival mechanisms to keep the cell proliferative potential. The Warburg effect directs the cellular metabolism towards an aerobic glycolytic pathway, despite the fact that it generates less adenosine triphosphate than oxidative phosphorylation; because it creates the building blocks necessary for cell proliferation. The transcription factor p53 is the master tumor suppressor; it binds to more than 4,000 sites in the genome and regulates the expression of more than 500 genes. Among these genes are important regulators of metabolism, affecting glucose, lipids and amino acids metabolism, oxidative phosphorylation, reactive oxygen species (ROS) generation and growth factors signaling. Wild-type and mutant p53 may have opposing effects in the expression of these metabolic genes. Therefore, depending on the p53 status of the cell, drugs that target metabolism may have different outcomes and metabolism may modulate drug resistance. Conversely, induction of p53 expression may regulate differently the tumor cell metabolism, inducing senescence, autophagy and apoptosis, which are dependent on the regulation of the PI3K/AKT/mTOR pathway and/or ROS induction. The interplay between p53 and metabolism is essential in the decision of cell fate and for cancer therapeutics.

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“…e P72R polymorphism is present in the segment encoding the transactivation domain and may increase the expression of this gene and the levels of anti-TP53 antibodies [28].…”

Section: Discussionmentioning

confidence: 99%

NOTCH3 T6746C and TP53 P72R Polymorphisms Are Associated with the Susceptibility to Diffuse Cutaneous Systemic Sclerosis

Zmorzyński

Wojcierowska-Litwin

Kowal

et al. 2020

BioMed Research International

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Introduction. NOTCH pathway and TP53 protein are involved in the development of fibrosis and autoimmune disorders, respectively. The aim of this study was to evaluate the role of single nucleotide polymorphisms (SNPs) of NOTCH3 and TP53 genes and serum anti-TP53 antibodies with the susceptibility, clinical subset of systemic sclerosis (SSc), and clinical profile of SSc patient, particularly with lung involvement and disease activity. Objects and Methods. 124 white Polish SSc patients (101 with limited cutaneous SSc–lcSSc, and 23 with diffuse cutaneous SSc–dcSSc) and 100 healthy individuals were included in the study. Patients were assessed for the presence of autoantibodies and interstitial lung disease. Two SNPs at position 6746 of NOTCH3 gene (C/T alleles) and 215 of the TP53 gene (P/R alleles) were genotyped by PCR-restriction fragment length polymorphism. Serum levels of anti-TP53 antibodies were analyzed by means of ELISA. Results. The genotypic frequencies of the NOTCH3 gene for SSc patients diverged significantly from Hardy–Weinberg equilibrium (p=0.03; χ2 = 4.63). There was no significant difference between SSc patients and the control population in allele frequencies of both SNPs. The CT + CC genotypes of NOTCH3 influenced the susceptibility to SSc (OR = 1.85, p=0.04), including dcSSc (OR = 3.43, p=0.04), and active form of SSc (OR = 5.46, p<0.001). The PR + RR genotypes of the TP53 gene were associated only with dcSSc susceptibility (OR = 3.30, p=0.034). The levels of anti-TP53 antibodies were not related to studied SNPs and clinical parameters of SSc including the presence of specific antibodies and interstitial lung disease. Conclusion. The CT + CC genotypes of NOTCH3 gene and PR + RR genotypes of the TP53 gene increased the risk of dcSSc development. Moreover, genotypes of CT + CC were associated with the active form of SSc suggesting the role of the NOTCH pathway in the pathogenesis of this disease.

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Different TP53 mutants in p53 overexpressed epithelial ovarian carcinoma can be associated both with altered and unaltered glycolytic and apoptotic profiles

Cited by 13 publications

References 30 publications

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

p53 and metabolism: from mechanism to therapeutics

NOTCH3 T6746C and TP53 P72R Polymorphisms Are Associated with the Susceptibility to Diffuse Cutaneous Systemic Sclerosis

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