Hyperphosphorylation of PP2A in colorectal cancer and the potential therapeutic value showed by its forskolin-induced dephosphorylation and activation

Cristóbal, Ion; Rincón, Raúl; Manso, Rebeca; Madoz‐Gúrpide, Juan; Caramés, Cristina; Puerto‐Nevado, Laura del; Rojo, Federico; Garcı́a-Foncillas, Jesús

doi:10.1016/j.bbadis.2014.06.032

Cited by 31 publications

(23 citation statements)

References 24 publications

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“…Media were supplemented with penicillin G (100 U/ml), and streptomycin (0.1 mg/ml). Cells were treated with oxaliplatin (LOHP) (1 μM) (Sigma), 5-fluorouracil (5-FU) (1 μM) (Sigma) and FTY720 (10 μM) (Calbiochem) as previously reported [6, 9]. For transfection experiments, CRC cells were seeded in 6-well plates and transfected with 10 μl of Lipofectamine 2000 (Life Technologies) and 2 μg of SET plasmidic vector or 20 nM of a miR-199b specific mir Vana™ miRNA Mimic and Inhibitor (Ambion).…”

Section: Methodsmentioning

confidence: 99%

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Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

et al. 2016

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The tumor suppressor microRNA-199b (miR-199b) is a negative SET regulator associated with poor outcome in some human cancers. However, its expression levels as well as potential biological and clinical significance in colorectal cancer (CRC) remain completely unexplored. The PP2A inhibitor SET has shown promising therapeutic and clinical implications in metastatic CRC (mCRC) but the molecular mechanisms underlying SET deregulation are currently unknown. We show here miR-199b downregulation in 4 out of 5 CRC SET-overexpressing cell lines and its inverse correlation with SET overexpression in CRC patients. Moreover, miR-199b led to PP2A activation through a direct SET inhibition, impaired cell viability and enhanced oxaliplatin sensitivity in CRC cells. MiR-199b was found downregulated in 25% of cases, and associated with lymph metastasis (p = 0.049), presence of synchronous metastasis at diagnosis (p = 0.026) and SET overexpression (p < 0.001). Furthermore, low miR-199b levels determined shorter overall (p < 0.001), progression-free survival (p = 0.003) and predicted clinical benefit to oxaliplatin treatment. The miR-199b prognostic impact was particularly evident in both younger and KRAS wild-type subgroups. Multivariate analyses confirmed its independent prognostic impact. Altogether, our results show that miR-199b is a tumor suppressor whose downregulation independently determines worse outcome and emerges as a potential contributing mechanism to inhibit PP2A via SET overexpression in a subgroup of mCRC patients.

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Section: Methodsmentioning

confidence: 99%

“…Several works highlighting the molecular and clinical significance of PP2A inhibition in CRC have been reported [6–9]. The protein SET is a potent endogenous PP2A inhibitor [10] involved in many cell functions [11–15] and a novel proposed target for anticancer therapy [16].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

et al. 2016

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“…Media were supplemented with penicillin G (100 U/mL) and streptomycin (0.1 mg/mL). Cells were treated with oxaliplatin (LOHP; 1 mmol/L; Sigma) and FTY720 (10 mmol/L; Calbiochem) as previously reported (32)(33)(34). For transfection experiments, colorectal cancer cells were seeded in 6-well plates and transfected with 10 mL of Lipofectamine 2000 (Life Technologies) and 2 mg of plasmidic vectors or 75 nmol/L of SET-specific siRNAs designed and synthesized by Dharmacon RNA Technologies.…”

Section: Cell Cultures and Transfectionmentioning

confidence: 99%

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

Cristóbal

Rincón

Manso

et al. 2015

Clinical Cancer Research

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Purpose: SET is an endogenous PP2A inhibitor that might represent a novel molecular target for antitumor therapy. The aim of this study was to evaluate the molecular effects of SET deregulation and its potential clinical significance in metastatic colorectal cancer (mCRC).Experimental Design: We studied the biologic effects of SET on cell growth, colonosphere formation, caspase activity, PP2A activation status, and sensitivity to oxaliplatin and FTY720 treatments. Moreover, we analyzed SET expression by immunostaining in 242 patients with mCRC.Results: SET deregulation promotes cell growth and colonosphere formation and inhibits PP2A, thereby impairing its antitumor effects. Moreover, SET reduces sensitivity to oxaliplatin in colorectal cancer cell lines, which is restored after FTY720 treatment. SET overexpression was detected in 24.8% (60 of 242) of patients with mCRC and determined significantly shorter overall (8.6 vs. 27 months; P < 0.001) and progression-free survival (7.1 vs. 13.7 months; P < 0.001), and poor response to oxaliplatin-based chemotherapy (P ¼ 0.004). Interestingly, its prognostic value was particularly evident in patients younger than 70 years and in those harboring KRAS mutations.Conclusions: SET overexpression is a frequent event in mCRC that plays a potential oncogenic role associated with worse outcome and resistance to oxaliplatin. Moreover, this alteration defines a subgroup of patients who could benefit from therapies containing PP2A activators such as FTY720.

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“…HL60 cells were exposed to carfilzomib at 100 nmol/l for 24 h then fixed for chromatin immunoprecipitation (ChIP) assay. On the other hand, forskolin treatment reduces the phosphorylation of the C-terminal tail PP2A C subunit Y307, thereby activating PP2A (Feschenko et al, 2002;Cristobal et al, 2011Cristobal et al, , 2014. Then, KIAA1524 promoter fragments were amplified by PCR.…”

Section: Discussionmentioning

confidence: 99%

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

et al. 2017

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Enhancing the tumour suppressive activity of protein phosphatase 2A (PP2A) has been suggested to be an anti-leukaemic strategy. KIAA1524 (also termed CIP2A), an oncoprotein inhibiting PP2A, is associated with disease progression in chronic myeloid leukaemia and may be prognostic in cytogenetically normal acute myeloid leukaemia. Here we demonstrated that the selective proteasome inhibitor, carfilzomib, induced apoptosis in sensitive primary leukaemia cells and in sensitive leukaemia cell lines, associated with KIAA1524 protein downregulation, increased PP2A activity and decreased p-Akt, but not with the proteasome inhibition effect of carfilzomib. Ectopic expression of KIAA1524, or pretreatment with the PP2A inhibitor, okadaic acid, suppressed carfilzomib-induced apoptosis and KIAA1524 downregulation in sensitive cells, whereas co-treatment with the PP2A agonist, forskolin, enhanced carfilzomib-induced apoptosis in resistant cells. Mechanistically, carfilzomib affected KIAA1524 transcription through disturbing ELK1 (Elk-1) binding to the KIAA1524 promoter. Moreover, the drug sensitivity and mechanism of carfilzomib in xenograft mouse models correlated well with the effects of carfilzomib on KIAA1524 and p-Akt expression, as well as PP2A activity. Our data disclosed a novel drug mechanism of carfilzomib in leukaemia cells and suggests the potential therapeutic implication of KIAA1524 in leukaemia treatment.

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Hyperphosphorylation of PP2A in colorectal cancer and the potential therapeutic value showed by its forskolin-induced dephosphorylation and activation

Cited by 31 publications

References 24 publications

Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

Downregulation of microRNA-199b predicts unfavorable prognosis and emerges as a novel therapeutic target which contributes to PP2A inhibition in metastatic colorectal cancer

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

Carfilzomib induces leukaemia cell apoptosis via inhibitingELK1/KIAA1524 (Elk‐1/CIP2A) and activatingPP2A not related to proteasome inhibition

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