PTEN: Its Deregulation and Tumorigenesis

Maehama, Tomohiko

doi:10.1248/bpb.30.1624

Cited by 58 publications

(56 citation statements)

References 81 publications

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“…However, our results confirmed the expected effects of PTEN silencing on the regulation of PI3K/AKT and MAPK signaling pathways, in agreement with already reported data (35,36). Indeed, PTEN silencing in Cal 27 cells led to a constitutive activation of signaling pathways evidenced by a strong increase in pAKT and pERK 1/2 expression, though without inducing any significant promotion of proliferation or cell viability.…”

Section: Discussionsupporting

confidence: 93%

Cellular response to cetuximab in PTEN-silenced head and neck squamous cell carcinoma cell line

Mriouah¹,

Boura²,

Pinel³

et al. 2010

Int J Oncol

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Abstract. The implication of loss of PTEN expression in resistance to targeted therapy has already been described in many tumor types. The absence of response to anti-EGFR agents in PTEN-deficient tumors relies on persistent activation of signaling pathways downstream of pEGFR. To investigate the role of PTEN loss of expression in head and neck squamous cell carcinoma (HNSCC) response to cetuximab, we used siRNA in Cal 27 cells and then evaluated key signaling protein activation (pAKT and pERK 1/2) as well as cell viability and proliferation. PTEN silencing in Cal 27 cells led to a constitutive activation of signaling pathways evidenced by a strong increase in pAKT and pERK 1/2 expression. Moreover, PTEN-silenced cells did not show any significant changes either in cell viability or proliferation, only slight modifications on cell cycle. Additionally and unpredictably, our results indicated that PTEN silencing, led to a drastic reduction in pEGFR expression whereas total EGFR level did not significantly vary. Strikingly, despite this overactivation of signaling pathways ruling cell survival and proliferation in siPTEN cells, cetuximab fully exerted pAKT and pERK 1/2 inhibition of expression, similarly to its effect in untransfected Cal 27 cells. In conclusion, our study established that in Cal 27 cells, cetuximab keeps full ability to inhibit EGFR-dependent mechanisms, as shown by a decreased pAKT and pERK 1/2 level of expression, despite a strong PTEN silencing-induced overactivation. In Cal 27 cells, loss of PTEN expression does not lead to a loss of cetuximab efficacy in inhibiting EGFRdownstream signaling pathways, contrarily to data shown in previous works conducted in other tumor types.

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Section: Discussionsupporting

confidence: 93%

Cellular response to cetuximab in PTEN-silenced head and neck squamous cell carcinoma cell line

Mriouah¹,

Boura²,

Pinel³

et al. 2010

Int J Oncol

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“…Pten heterozygosity and tissue-specific deletion in mice leads to hyperplastic and dysplasic changes in the prostate, colon, and skin, and to spontaneous tumor development, supporting the notion that PTEN plays a causal role in hamartoma syndromes (13)(14)(15)(16)(17)(18)(19). Cells exhibiting decreased PTEN activity are not able to restrain the growth promoting properties of PI3K and its lipid product, PIP 3 (10,11,20). One of the best studied downstream targets of PI3K is the serine-threonine kinase Akt, which, upon activation by PIP 3 , promotes cell proliferation and survival by phosphorylating multiple protein targets, thereby controlling cell growth, protein translation, cell metabolism, and program cell death (21,22).…”

Section: Introductionmentioning

confidence: 72%

“…PTEN encodes a lipid phosphatase, PTEN, which is a negative regulator of the phosphatidylinositol 3-kinase (PI3K) pathway by converting phosphatidylinositol 3,4,5-triphosphate (PIP 3 ) into phosphatidylinositol 4,5-biphosphate (PIP 2 ; refs. [9][10][11]. Underscoring the importance of PTEN as a tumor suppressor gene, germline mutations of PTEN have been linked to several autosomal dominant hamartoma syndromes including Cowden's disease (Omim:308350), BannayanRiley-Ruvalcaba syndrome (OMIM:153480), and Lhermitte-Duclos syndrome (OMIM:158350), which are all characterized by the presence of benign tumors, known as hamartomas, in multiple organs and an increased susceptibility to developing a variety of malignancies (reviewed in ref.…”

Section: Introductionmentioning

confidence: 99%

“…In the case of Cowden's disease, PTEN germline mutations are found in 80% of the patients, either in the PTEN coding sequence, in the PTEN promoter, or in its 5 ¶ and 3 ¶ untranslated region resulting in inhibition of translation or a catalytically inactive, immature, or unstable PTEN protein, which may undergo rapid degradation (10,12). Pten heterozygosity and tissue-specific deletion in mice leads to hyperplastic and dysplasic changes in the prostate, colon, and skin, and to spontaneous tumor development, supporting the notion that PTEN plays a causal role in hamartoma syndromes (13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

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Chemoprevention and Treatment of Experimental Cowden's Disease by mTOR Inhibition with Rapamycin

2008

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“…PTEN can inhibit cell proliferation, promote apoptosis and suppress angiogenesis in many cancers. 32,33 Recently, it has been shown that PTEN is a downstream target gene for PPARg, 34 and upregulation of PTEN by PPARg ligands such as rosiglitazone was probably responsible for the anticancer effects of these ligands. 35 Our in vitro study showed that rosiglitazone barely altered the expression of PTEN when XIAP is present, whereas this agent could significantly upregulate the expression of PTEN when XIAP was knocked out (HCT116-XIAP 2/2 cells).…”

Section: Discussionmentioning

confidence: 99%

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

Dai

Qiao

Chan

et al. 2008

Intl Journal of Cancer

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Ligands for peroxisome proliferator-activated receptor gamma (PPARc) possess anticancer properties. However, the efficacy of PPARc ligands varies in different cancers. In colon cancer, the role of PPARc and its ligands is controversial. We recently showed that downregulation of X-linked inhibitor of apoptosis protein (XIAP) could sensitize colon cancer cells to troglitazone, and 15-deoxy-D12,14-prostaglandin J2 (15-PGJ2) induced cell killing. In our study, we aimed to examine whether rosiglitazone, another more clinically relevant PPARc ligand, has any synergistic anticancer effect with XIAP downregulation in colon cancer. Human colon cancer cell lines HCT116-XIAP 1/1 cells and HCT116-XIAP 2/2 cells were treated with various concentrations of rosiglitazone. The effects of rosiglitazone on cell proliferation, apoptosis and growth of xenograft colon cancers were studied. Rosiglitazone barely suppressed the growth and only very weakly induced apoptosis in HCT116 cells in vitro. Loss of XIAP did not sensitize HCT116 cells to rosiglitazone-induced growth inhibition or apoptosis. In vivo studies revealed that rosiglitazone strongly suppressed the growth of xenograft colon cancer, especially tumors derived from HCT116-XIAP 2/2 cells. The rosiglitazone-treated tumor had reduced expression of ki-67 and lowered mitotic rate. Downregulation of XIAP was associated with an impaired activation of PPARc by its ligand. Rosiglitazone induced marked upregulation of PTEN in HCT116-XIAP 2/2 cells, as well as in xenograft tumors derived from HCT116-XIAP 2/2 cells. We concluded that rosiglitazone significantly suppresses the growth of xenograft colon cancer, and downregulation of XIAP sensitizes the xenograft tumors to rosiglitazone-induced tumor suppression in vivo via upregulation of PTEN.

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PTEN: Its Deregulation and Tumorigenesis

Cited by 58 publications

References 81 publications

Cellular response to cetuximab in PTEN-silenced head and neck squamous cell carcinoma cell line

Cellular response to cetuximab in PTEN-silenced head and neck squamous cell carcinoma cell line

Chemoprevention and Treatment of Experimental Cowden's Disease by mTOR Inhibition with Rapamycin

Loss of XIAP sensitizes rosiglitazone‐induced growth inhibition of colon cancer in vivo

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