Prostate cancer, PI3K, PTEN and prognosis

2017 ◽  
Vol 131 (3) ◽  
pp. 197-210 ◽  
Author(s):  
Helen M. Wise ◽  
Miguel A. Hermida ◽  
Nicholas R. Leslie
Keyword(s):  
Prostate Cancer ◽  
Loss Of Function ◽  
Prostate Cancer Treatment ◽  
Pten Loss ◽  
Genomic Deletions ◽  
Lipid Phosphatase ◽  
Signalling Network ◽  
Prostate Cancer Development ◽  
Pi3k Signalling ◽  
Phosphoinositide 3 Kinase

Loss of function of the PTEN tumour suppressor, resulting in dysregulated activation of the phosphoinositide 3-kinase (PI3K) signalling network, is recognized as one of the most common driving events in prostate cancer development. The observed mechanisms of PTEN loss are diverse, but both homozygous and heterozygous genomic deletions including PTEN are frequent, and often accompanied by loss of detectable protein as assessed by immunohistochemistry (IHC). The occurrence of PTEN loss is highest in aggressive metastatic disease and this has driven the development of PTEN as a prognostic biomarker, either alone or in combination with other factors, to distinguish indolent tumours from those likely to progress. Here, we discuss these factors and the consequences of PTEN loss, in the context of its role as a lipid phosphatase, as well as current efforts to use available inhibitors of specific components of the PI3K/PTEN/TOR signalling network in prostate cancer treatment.

scholarly journals Overview of the Development and Use of Akt Inhibitors in Prostate Cancer

2021 ◽  
Vol 11 (1) ◽  
pp. 160
Author(s):  
Anis Gasmi ◽  
Guilhem Roubaud ◽  
Charles Dariane ◽  
Eric Barret ◽  
Jean-Baptiste Beauval ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trials ◽  
Phase Ii ◽  
Critical Role ◽  
Castration Resistant Prostate Cancer ◽  
Loss Of Function ◽  
Pten Loss ◽  
Castration Resistant ◽  
Recent Phase ◽  
Phase Ii And Iii

Deregulation of the PI3K-Akt-mTOR pathway plays a critical role in the development and progression of many cancers. In prostate cancer, evidence suggests that it is mainly driven by PTEN loss of function. For many years, the development of selective Akt inhibitors has been challenging. In recent phase II and III clinical trials, Ipatasertib and Capivasertib associated with androgen deprivation therapies showed promising outcomes in patients with metastatic castration-resistant prostate cancer and PTEN-loss. Ongoing trials are currently assessing several Akt inhibitors in prostate cancer with different combinations, at different stages of the disease.

scholarly journals Both p110α and p110β isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor

2012 ◽  
Vol 442 (1) ◽  
pp. 151-159 ◽  
Author(s):  
Inma M. Berenjeno ◽  
Julie Guillermet-Guibert ◽  
Wayne Pearce ◽  
Alexander Gray ◽  
Stewart Fleming ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Tumour Suppressor ◽  
Negative Regulator ◽  
Cancer Development ◽  
Pten Loss ◽  
Mouse Tissues ◽  
Primary Mouse ◽  
Prostate Cancer Development ◽  
The Impact

The PI3K (phosphoinositide 3-kinase) pathway is commonly activated in cancer as a consequence of inactivation of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), a major negative regulator of PI3K signalling. In line with this important role of PTEN, mice that are heterozygous for a PTEN-null allele (PTEN+/− mice) spontaneously develop a variety of tumours in multiple organs. PTEN is a phosphatase with selectivity for PtdIns(3,4,5)P3, which is produced by the class I isoforms of PI3K (p110α, p110β, p110γ and p110δ). Previous studies indicated that PTEN-deficient cancer cell lines mainly depend on p110β, and that p110β, but not p110α, controls mouse prostate cancer development driven by PTEN loss. In the present study, we investigated whether the ubiquitously expressed p110α can also functionally interact with PTEN in cancer. Using genetic mouse models that mimic systemic administration of p110α- or p110β-selective inhibitors, we confirm that inactivation of p110β, but not p110α, inhibits prostate cancer development in PTEN+/− mice, but also find that p110α inactivation protects from glomerulonephritis, pheochromocytoma and thyroid cancer induced by PTEN loss. This indicates that p110α can modulate the impact of PTEN loss in disease and tumourigenesis. In primary and immortalized mouse fibroblast cell lines, both p110α and p110β controlled steady-state PtdIns(3,4,5)P3 levels and Akt signalling induced by heterozygous PTEN loss. In contrast, no correlation was found in primary mouse tissues between PtdIns(3,4,5)P3 levels, PI3K/PTEN genotype and cancer development. Taken together, our results from the present study show that inactivation of either p110α or p110β can counteract the impact of PTEN inactivation. The potential implications of these findings for PI3K-targeted therapy of cancer are discussed.

Metabolic switching of PI3K-dependent lipid signals

2007 ◽  
Vol 35 (2) ◽  
pp. 188-192 ◽  
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.

scholarly journals HMGB1: A Promising Therapeutic Target for Prostate Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Munirathinam Gnanasekar ◽  
Ramaswamy Kalyanasundaram ◽  
Guoxing Zheng ◽  
Aoshuang Chen ◽  
Maarten C. Bosland ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
High Mobility ◽  
Chromatin Binding ◽  
Oncogenic Signaling ◽  
Prostate Cancer Treatment ◽  
Promising Therapeutic Target ◽  
Prostate Cancer Development ◽  
Oncogenic Signaling Pathways

High mobility group box 1 (HMGB1) was originally discovered as a chromatin-binding protein several decades ago. It is now increasingly evident that HMGB1 plays a major role in several disease conditions such as atherosclerosis, diabetes, arthritis, sepsis, and cancer. It is intriguing how deregulation of HMGB1 can result in a myriad of disease conditions. Interestingly, HMGB1 is involved in cell proliferation, angiogenesis, and metastasis during cancer progression. Furthermore, HMGB1 has been demonstrated to exert intracellular and extracellular functions, activating key oncogenic signaling pathways. This paper focuses on the role of HMGB1 in prostate cancer development and highlights the potential of HMGB1 to serve as a key target for prostate cancer treatment.

1077: A Novel Apoptosis-Inducing Gene and its Application in Prostate Cancer Treatment

2004 ◽  
Vol 171 (4S) ◽  
pp. 284-284
Author(s):  
Yi Lu ◽  
Jun Zhang ◽  
Ben Beheshti ◽  
Ximing J. Yang ◽  
Syamal K. Bhattacharya ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Treatment ◽  
Prostate Cancer Treatment
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