PI3K/Akt-mediated regulation of p53 in cancer

Mutations activating the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway and inactivating the TP53 tumour-suppressor gene are common mechanisms that cancer cells require to proliferate and escape pre-programmed cell death. In a well-described mechanism, Akt mediates negative control of p53 levels through enhancing MDM2 (murine double minute 2)-mediated targeting of p53 for degradation. Accumulating evidence is beginning to suggest that, in certain circumstances, PTEN (phosphatase and tensin homologue deleted on chromosome 10)/PI3K/Akt also promotes p53 translation and protein stability, suggesting that additional mechanisms may be involved in the Akt-mediated regulation of p53 in tumours. In the present article, we discuss these aspects in the light of clinical PI3K/Akt inhibitors, where information regarding the effect on p53 activity will be a crucial factor that will undoubtedly influence therapeutic efficacy.

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Metabolic switching of PI3K-dependent lipid signals

Biochemical Society Transactions ◽

10.1042/bst0350188 ◽

2007 ◽

Vol 35 (2) ◽

pp. 188-192 ◽

Cited By ~ 12

Author(s):

C.P. Downes ◽

N.R. Leslie ◽

I.H. Batty ◽

J. van der Kaay

Keyword(s):

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Metabolic Switch ◽

Inositol Phosphatase ◽

Lipid Phosphatase ◽

Metabolic Switching ◽

Pi3k Signalling ◽

Src Homology ◽

Phosphoinositide 3 Kinase ◽

Phosphatase And Tensin Homologue

The lipid phosphatase, PTEN (phosphatase and tensin homologue deleted on chromosome 10), is the product of a major tumour suppressor gene that antagonizes PI3K (phosphoinositide 3-kinase) signalling by dephosphorylating the 3-position of the inositol ring of PtdIns(3,4,5)P3. PtdIns(3,4,5)P3 is also metabolized by removal of the 5-phosphate catalysed by a distinct family of enzymes exemplified by SHIP1 [SH2 (Src homology 2)-containing inositol phosphatase 1] and SHIP2. Mouse knockout studies, however, suggest that PTEN and SHIP2 have profoundly different biological functions. One important reason for this is likely to be that SHIP2 exists in a relatively inactive state until cells are exposed to growth factors or other stimuli. Hence, regulation of SHIP2 is geared towards stimulus dependent antagonism of PI3K signalling. PTEN, on the other hand, appears to be active in unstimulated cells and functions to maintain basal PtdIns(3,4,5)P3 levels below the critical signalling threshold. We suggest that concomitant inhibition of cysteine-dependent phosphatases, such as PTEN, with activation of SHIP2 functions as a metabolic switch to regulate independently the relative levels of PtdIns(3,4,5)P3 and PtdIns(3,4)P2.

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MDM2 Amplified Sarcomas: A Literature Review

Diagnostics ◽

10.3390/diagnostics11030496 ◽

2021 ◽

Vol 11 (3) ◽

pp. 496

Author(s):

Raf Sciot

Keyword(s):

Suppressor Gene ◽

Negative Regulator ◽

Low Grade ◽

P53 Mutations ◽

Lipomatous Tumor ◽

Double Minute ◽

Genetic Features ◽

Murine Double Minute ◽

Well Differentiated ◽

Mdm2 Amplification

Murine Double Minute Clone 2, located at 12q15, is an oncogene that codes for an oncoprotein of which the association with p53 was discovered 30 years ago. The most important function of MDM2 is to control p53 activity; it is in fact the best documented negative regulator of p53. Mutations of the tumor suppressor gene p53 represent the most frequent genetic change in human cancers. By overexpressing MDM2, cancer cells have another means to block p53. The sarcomas in which MDM2 amplification is a hallmark are well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma, intimal sarcoma, and low-grade osteosarcoma. The purpose of this review is to summarize the typical clinical, histopathological, immunohistochemical, and genetic features of these tumors.

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Apoptosis and metastasis: a superior resistance of metastatic cancer cells to programmed cell death

Cancer Letters ◽

10.1016/0304-3835(96)04112-2 ◽

1996 ◽

Vol 101 (1) ◽

pp. 43-51 ◽

Cited By ~ 76

Author(s):

Gennadi V. Glinsky ◽

Vladislav V. Glinsky

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cancer Cells ◽

Metastatic Cancer ◽

Metastatic Cancer Cells

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BH3-only proteins are essential initiators of programmed cell death and stress-induced apoptosis in normal and cancer cells

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(08)71195-9 ◽

2008 ◽

Vol 6 (9) ◽

pp. 6

Author(s):

A. Strasser ◽

A. Villunger ◽

P. Bouillet ◽

E.M. Michalak ◽

L.A. O'Reilly ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cancer Cells ◽

Induced Apoptosis

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Methylglyoxal at metronomic doses sensitizes breast cancer cells to doxorubicin and cisplatin causing synergistic induction of programmed cell death and inhibition of stemness

Biochemical Pharmacology ◽

10.1016/j.bcp.2018.08.041 ◽

2018 ◽

Vol 156 ◽

pp. 322-339 ◽

Cited By ~ 8

Author(s):

Anirban Roy ◽

Sushmita Sarker ◽

Priyanka Upadhyay ◽

Aparajita Pal ◽

Arghya Adhikary ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Programmed Cell Death ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Synergistic Induction

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Regulation of programmed cell death by plasminogen activator inhibitor type 1 (PAI-1)

Thrombosis and Haemostasis ◽

10.1160/th08-04-0266 ◽

2008 ◽

Vol 100 (12) ◽

pp. 1041-1046 ◽

Cited By ~ 23

Author(s):

Maria Rømer ◽

Ulrik A. Lademann

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Cancer Cells ◽

Plasminogen Activator ◽

Cell Signalling ◽

Plasminogen Activator Inhibitor ◽

Plasminogen Activator Inhibitor 1 ◽

Activator Inhibitor Type ◽

Activator Inhibitor ◽

Pai 1

SummaryElevated levels of plasminogen activator inhibitor-1 (PAI-1) are associated with poor prognosis in cancer. An explanation to the elevated levels of PAI-1 could be a protective response to the increased proteolytic activity, caused by elevated levels of urokinase-type plasminogen activator (uPA) observed in tumours; however, several lines of evidence suggest that PAI-1 may contribute directly to the pathology of the disease. PAI-1 has been reported to have an effect on most of the basic cellular processes including cell adhesion, cell migration, cell invasion, and cell proliferation and increasing numbers of reports suggest that PAI-1 also can regulate programmed cell death (PCD) in cancer cells and normal cells.A number of reports suggest that PAI-1 can inhibit PCD through its pro-adhesive/anti-proteolytic property whereas other reports suggest that PAI-1 induces PCD through its anti-adhesive property.Furthermore,it has been suggested that PAI-1 can either induce or inhibit PCD though activation of cell signalling pathways.This review will focus on the regulation of programmed cell death by PAI-1 in both normal cells and cancer cells.

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Selective Suppression of Cell Growth and Programmed Cell Death-Ligand 1 Expression in HT1080 Fibrosarcoma Cells by Low Molecular Weight Fucoidan Extract

Marine Drugs ◽

10.3390/md17070421 ◽

2019 ◽

Vol 17 (7) ◽

pp. 421 ◽

Cited By ~ 3

Author(s):

Kiichiro Teruya ◽

Yoshihiro Kusumoto ◽

Hiroshi Eto ◽

Noboru Nakamichi ◽

Sanetaka Shirahata

Keyword(s):

Molecular Weight ◽

Cell Death ◽

Programmed Cell Death ◽

Cancer Cells ◽

Biological Activities ◽

Immune Surveillance ◽

Selective Inhibition ◽

Low Molecular Weight ◽

Fibrosarcoma Cells ◽

Self Protection

Low molecular weight fucoidan extract (LMF), prepared by an abalone glycosidase digestion of a crude fucoidan extracted from Cladosiphon novae-caledoniae Kylin, exhibits various biological activities, including anticancer effect. Various cancers express programmed cell death-ligand 1 (PD-L1), which is known to play a significant role in evasion of the host immune surveillance system. PD-L1 is also expressed in many types of normal cells for self-protection. Previous research has revealed that selective inhibition of PD-L1 expressed in cancer cells is critical for successful cancer eradication. In the present study, we analyzed whether LMF could regulate PD-L1 expression in HT1080 fibrosarcoma cells. Our results demonstrated that LMF suppressed PD-L1/PD-L2 expression and the growth of HT1080 cancer cells and had no effect on the growth of normal TIG-1 cells. Thus, LMF differentially regulates PD-L1 expression in normal and cancer cells and could serve as an alternative complementary agent for treatment of cancers with high PD-L1 expression.

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