Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival

Sawai, Hirozumi; Yasuda, Akira; Ochi, Nobuo; Ma, Jiachi; Matsuo, Yoichi; Wakasugi, Takehiro; Takahashi, Hiroki; Funahashi, Hitoshi; Sato, Mikinori; Takeyama, Hiromitsu

doi:10.1186/1471-230x-8-56

Cited by 111 publications

(88 citation statements)

References 33 publications

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“…Interestingly, one of the more sensitive lines, MDA-MB-157, expressed mutant rac (16). Loss of PTEN expression is common across many tumor types, TNBC (9), prostate (10,11), head and neck (21), colorectal cancer (22,23), and squamous lung (24), suggesting that inhibitors of PI3Kb are relevant in many diseases. Gaining insight into why PTEN WT cells are sensitive will broaden the application of these differentiated PI3K inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Given treatment with AD8186 has the potential to induce feedback through FOXO-regulated genes activating other pro-proliferative signaling pathways (21,23), intermittent pathway suppression could reduce the feedback loop-induced resistance as a result of upregulation of IGF-R-, IRS-2-, or ERB-mediated signaling as seen with AKT inhibitors (25,26,27). Moreover, when combining with other agents, being able to schedule each therapy to maximize therapeutic index is also an advantage (3).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kb isoform. Inhibitors of PI3Kb have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kb and PI3Kd (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI 50 < 1 mmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kb with activity against PI3Kd signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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“…It has been reported that loss of function or downregulation of PTEN resulted in tumor metastasis, and more aggressive growth behaviors of tumor, and/or poor prognostic phenotypes. 42,[49][50][51][52][53][54][55][56][57] In addition, miR-19 upregulation was observed in various cancers including lung cancer, and correlated with tumor metastasis and/or poor prognosis of cancer patients. [11][12][13][14][15]18 Given that miRNAs primarily function through inhibiting the translation of their mRNA targets, we propose that miR-19 might be a negative regulator for PTEN, which has been reported by other researchers.…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence supports that inactivation or downregulation of the tumor suppressor PTEN can trigger EMT of cancer cells, [60][61][62][63] which then promoted the invasion and metastasis of various cancers including lung cancer. 42,[49][50][51][52][53][54][55][56][57] It has been reported that PTEN negatively regulated the PI3K/ Akt pathway through the dephosphorylation of PI(3,4,5)P3, and ultimately participated in the regulation of cell cycle, proliferation, apoptosis, adhesion, and EMT during cancer progress. 63 In the present study, we found that PTEN silence through RNA interference mimicked miR-19-induced EMT, and promoted the migration and invasion of tumor cells, which were similar as the results caused by miR-19 overexpression.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

Yang

Yan

et al. 2015

Laboratory Investigation

100

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The miR-19 family (miR-19a and miR-19b-1) are key oncogenic components of the miR-17-92 cluster. Overexpression of miR-19 is strongly associated with cancer invasion and metastasis, and poor prognosis of cancer patients. However, the underlying mechanisms remain largely unknown. In the present study, we found that enforced expression of miR-19 including miR-19a and miR-19b-1 triggered epithelial-mesenchymal transition (EMT) of lung cancer cells A549 and HCC827 as shown by mesenchymal-like morphological conversion, downregulation of epithelial proteins (e.g., E-cadherin, ZO-1 (zona occludens 1), and α-catenin), upregulation of mesenchymal proteins (e.g., vimentin, fibronectin 1, N-cadherin, and snail1), formation of stress fibers, and reduced cell adhesion. In addition, enhanced migration and invasion were observed in the cancer cells A549 and HCC827 undergoing EMT. In contrast, silencing of endogenous miR-19 reversed EMT and reduced the migration and invasion abilities of A549 and HCC827 cells. DNA microarray results revealed significant changes of the expression of genes related to EMT, migration, and metastasis of miR-19-expressing A549 cells. Moreover, siRNA-mediated knockdown of PTEN, a target of miR-19, also resulted in EMT, migration, and invasion of A549 and HCC827 cells, suggesting that PTEN is involved in miR-19-induced EMT, migration and invasion of lung cancer cells. Furthermore, lung cancer cells undergoing EMT induced by miR-19 demonstrated reduced proliferation in vitro and in vivo, and enhanced resistance to apoptosis caused by TNF-α. Taken together, these findings suggest that miR-19 triggers EMT, which has an important role in the invasion and migration of lung cancer cells, accompanied by the reduced proliferation of cells.

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“…4a). The tumor suppressor PTEN is a common target for inactivation in cancer, including CRC (Rahal and Simmen 2010;Sawai et al 2008;Molinari and Frattini 2013). We next evaluated whether induction of PTEN is responsible, in part, for the inhibitory effects of MET, Gen, and Lun on colonosphere formation.…”

Section: Soy Bioactive Components Alter Hct116 Cell Viability Apoptomentioning

confidence: 99%

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

et al. 2015

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Colorectal cancer (CRC) is a disease whose genesis may include metabolic dysregulation. Cancer stem cells are attractive targets for therapeutic interventions since their aberrant expansion may underlie tumor initiation, progression, and recurrence. To investigate the actions of metabolic regulators on cancer stem cell-like cells (CSC) in CRC, we determined the effects of soybeanderived bioactive molecules and the anti-diabetes drug metformin (MET), alone and together, on the growth, survival, and frequency of CSC in human HCT116 cells. Effects of MET (60 lM) and soybean components genistein (Gen, 2 lM), lunasin (Lun, 2 lM), b-conglycinin (bcon, 3 lM), and glycinin (Gly, 3 lM) on HCT116 cell proliferation, apoptosis, and mRNA/protein expression and on the frequency of the CSC CD133 ? CD44 ? subpopulation by colonosphere assay and fluorescence-activated cell sorting/flow cytometry were evaluated. MET, Gen, and Lun, individually and together, inhibited HCT116 viability and colonosphere formation and, conversely, enhanced HCT116 apoptosis. Reductions in frequency of the CSC CD133 ? CD44 ? subpopulation with MET, Gen, and Lun were found to be associated with increased PTEN and reduced FASN expression. In cells under a hyperinsulinemic state mimicking metabolic dysregulation and without and with added PTEN-specific inhibitor SF1670, colonosphere formation and frequency of the CD133 ? CD44 ? subpopulation were decreased by MET, Lun and Gen, alone and when combined. Moreover, MET ? Lun ? Gen co-treatment increased the pro-apoptotic and CD133 ?-CD44 ? -inhibitory efficacy of 5-fluorouracil under hyperinsulinemic conditions. Results identify molecular networks shared by MET and bioavailable soy food components, which potentially may be harnessed to increase drug efficacy in diabetic and non-diabetic patients with CRC.

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Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival

Cited by 111 publications

References 33 publications

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

MicroRNA-19 triggers epithelial–mesenchymal transition of lung cancer cells accompanied by growth inhibition

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

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