The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Turnham, Daniel; Bullock, Nicholas; Dass, Manisha S.; Staffurth, John; Pearson, Helen

doi:10.3390/cells9112342

Cited by 56 publications

(38 citation statements)

References 393 publications

(515 reference statements)

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“…PCa is characterized by an activation of the PI3K-AKT-mTOR (phosphatidylinositol-3-kinase [PI3K], protein kinase B [PKB/AKT], and mTOR) pathway [ 131 ] and deficiency of PTEN (phosphatase and tensin homolog deleted on chromosome 10), a tumor suppressor gene that inhibits the PI3K-AKT-mTOR pathway, is associated with PCa [ 132 ]. Metformin is an AMPK activator and induces PTEN [ 133 ].…”

Section: Prostate-related Healthmentioning

confidence: 99%

The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review

Tseng

2022

World J Mens Health

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Metformin is the first-line oral antidiabetic drug that shows multiple pleiotropic effects of anti-inflamation, anti-cancer, anti-aging, anti-microbia, anti-atherosclerosis, and immune modulation. Metformin's effects on men's related health are reviewed here, focusing on reproductive health under subtitles of erectile dysfunction (ED), steroidogenesis and spermatogenesis; and on prostate-related health under subtitles of prostate specific antigen (PSA), prostatitis, benign prostate hyperplasia (BPH), and prostate cancer (PCa). Updated literature suggests a potential role of metformin on arteriogenic ED but controversial and contradictory effects (either protective or harmful) on testicular functions of testosterone synthesis and spermatogenesis. With regards to prostate-related health, metformin use may be associated with lower levels of PSA in humans, but its clinical implications require more research. Although there is a lack of research on metform's effect on prostatitis, it may have potential benefits through its anti-microbial and anti-inflammatory properties. Metformin may reduce the risk of BPH by inhibiting the insulin-like growth factor 1 pathway and some but not all studies suggest a protective role of metformin on the risk of PCa. Many clinical trials are being conducted to investigate the use of metformin as an adjuvant therapy for PCa but results currently available are not conclusive. While some trials suggest a benefit in reducing the metastasis and recurrence of PCa, others do not show any benefit. More research works are warranted to illuminate the potential usefulness of metformin in the promotion of men's health.

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Section: Prostate-related Healthmentioning

confidence: 99%

The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review

Tseng

2022

World J Mens Health

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“…This is in accordance with previous studies, showing that after HT treatment for 24 h, the cytotoxic effect depended on the Phosphate Tensin homolog ( PTEN ) status of the cell line [ 40 ]. PTEN is considered a tumor suppressor gene that is commonly mutated or deleted in PCa patients, leading to a functional loss, which is related with higher aggressiveness of the disease and a poorer clinical outcome [ 41 ]. In this sense, we observed that PTEN -null LNCaP and PC-3 cells (−/−) were most resistant, whereas the 22Rv1 cells (+/+) were the most sensitive.…”

Section: Resultsmentioning

confidence: 99%

Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells

et al. 2021

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A high adherence to a Mediterranean diet has been related to numerous beneficial effects in human health, including a lower incidence and mortality of prostate cancer (PCa). Olive oil is an important source of phenolic bioactive compounds, mainly hydroxytyrosol (HT), of this diet. Because of the growing interest of this compound and its derivatives as a cancer chemopreventive agent, we aimed to compare the in vitro effect of HT isolated from olive mill wastewaters and five semisynthetic alkyl ether, ester, and nitro-derivatives against prostate cancer (PCa) cell lines. The effect in cell proliferation was determined in RWPE-1, LNCaP, 22Rv1, and PC-3 cells by resazurin assay, the effect in cell migration by wound healing assay, and tumorsphere and colony formation were evaluated. The changes in key signaling pathways involved in carcinogenesis were assessed by using a phosphorylation pathway profiling array and by Western blotting. Antiproliferative effects of HT and two lipophilic derivatives [hydroxytyrosyl acetate (HT-Ac)/ethyl hydroxytyrosyl ether (HT-Et)] were significantly higher in cancerous PC-3 and 22Rv1 cells than in non-malignant RWPE-1 cells. HT/HT-Ac/HT-Et significantly reduced migration capacity in RWPE-1 and PC-3 and prostatosphere size and colony formation in 22Rv1, whereas only HT-Ac and HT-Et reduced these functional parameters in PC-3. The cytotoxic effect in 22Rv1 cells was correlated with modifications in the phosphorylation pattern of key proteins, including ERK1/2 and AKT. Consistently, HT-Ac and HT-Et decreased p-AKT levels in PC-3. In sum, our results suggest that HT and its lipophilic derivatives could be considered as potential therapeutic tools in PCa.

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“…Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K)-AKT (protein kinase B)-mammalian target of rapamycin complex 1 (mTORC1) pathway is a frequent finding in PCa that promotes tumorigenesis, tumor progression, and resistance to therapy [22,23] . PI3K-AKT-mTORC1 signaling is elevated in a high proportion of PCa and castration-resistant PCa (CRPC) [24][25][26][27] . Reduced expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a critical tumor suppressor of PCa, correlates with PCa progression and poor prognosis [28] .…”

Section: Genetic Deviations Activating Pi3k-akt-mtorc1 In Pcamentioning

confidence: 99%

“…Milk consumption has been related to several common mTORC1-driven cancers of Western civilization, especially PCa [166][167][168][169][170][171][172][173][174][175] , breast cancer [176][177][178][179][180][181][182][183] , hepatocellular carcinoma [184][185][186][187] , and diffuse large B-cell lymphoma [188] . Notably, overactivated mTORC1 signaling is a common hallmark of PCa [21,22,27,[57][58][59][60][61] , breast cancer [189][190][191][192][193][194] , hepatocellular carcinoma [195][196][197][198][199][200] , and diffuse large B-cell lymphoma [201][202][203][204] . Based on a recent review of the literature, Vasconcelos et al [154] confirmed a possible relationship between milk consumption and mTORC1-...…”

Section: Calcium-independent Milk-induced Mtorc1 Activationmentioning

confidence: 99%

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Melnik¹,

John²,

Weiskirchen³

et al. 2022

jtgg

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This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

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The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer

Cited by 56 publications

References 393 publications

The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review

The Effect of Metformin on Male Reproductive Function and Prostate: An Updated Review

Comparative Cytotoxic Activity of Hydroxytyrosol and Its Semisynthetic Lipophilic Derivatives in Prostate Cancer Cells

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

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