PP2A inhibition as a novel therapeutic target in castration-resistant prostate cancer

Gónzález-Alonso, Paula; Cristóbal, Ion; Manso, Rebeca; Madoz‐Gúrpide, Juan; Garcı́a-Foncillas, Jesús; Rojo, Federico

doi:10.1007/s13277-015-3849-5

Cited by 14 publications

(7 citation statements)

References 14 publications

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“…This is supported by our data showing that CIP2A overexpression or knockdown resulted in significant changes in genistein-induced cell cycle progression, growth inhibition and apoptosis. Moreover, our results also support CIP2A as a therapeutic target as it was reported in the studies on other anticancer agents ( 44 , 45 ).…”

Section: Discussionsupporting

confidence: 90%

Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells

Zhao

Parris

et al. 2016

International Journal of Oncology

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Genistein is a soy isoflavone with phytoestrogen and tyrosine kinase inhibitory properties. High intake of soy/genistein has been associated with reduced breast cancer risk. Despite the advances in genistein-mediated antitumor studies, the underlying mechanisms remain unclear. In the present study, we investigated genistein-induced regulation of the cancerous inhibitor of protein phosphatase 2A (CIP2A), a novel oncogene frequently overexpressed in breast cancer, and its functional impact on genistein-induced growth inhibition and apoptosis. We demonstrated that genistein induced downregulation of CIP2A in MCF-7-C3 and T47D breast cancer cells, which was correlated with its growth inhibition and apoptotic activities. Overexpression of CIP2A attenuated, whereas CIP2A knockdown sensitized, genistein-induced growth inhibition and apoptosis. We further showed that genistein-induced downregulation of CIP2A involved both transcriptional suppression and proteasomal degradation. In particular, genistein at higher concentrations induced concurrent downregulation of E2F1 and CIP2A. Overexpression of E2F1 attenuated genistein-induced downregulation of CIP2A mRNA, indicating the role of E2F1 in genistein-induced transcriptional suppression of CIP2A. Taken together, our results identified CIP2A as a functional target of genistein and demonstrated that modulation of E2F1-mediated transcriptional regulation of CIP2A contributes to its downregulation. These data advance our understanding of genistein-induced growth inhibition and apoptosis, and support further investigation on CIP2A as a therapeutic target of relevant anticancer agents.

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Section: Discussionsupporting

confidence: 90%

Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells

Zhao

Parris

et al. 2016

International Journal of Oncology

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“…Most prostate cancer patients have metastases at the time of diagnosis leading to decreased treatment outcomes and poor survival rates (3). Despite the advances in treatment approaches over the past few decades, the treatment outcome has not significantly improved (4,5), proliferation and apoptosis is responsible for the main reason of death, and many patients with prostate cancer can progress to metastatic disease finally (6). Thus uncovering the molecular mechanism of prostate cancer cell proliferation and apoptosis is urgent and important.…”

Section: Introductionmentioning

confidence: 99%

IL-8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NF-κB pathway in prostate cancer

Guo

Zang

et al. 2017

Molecular Medicine Reports

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Interleukin-8 (IL-8) possesses tumorigenic and proangiogenic properties, and is overexpressed in many human cancer types. However, only few studies have demonstrated the mechanisms of action of IL‑8 regarding the ability to promote proliferation and to inhibit apoptosis in prostate cancer. Here, the aim of the present study was to investigate the effects of IL‑8 on the prostate cancer cell line and determine possible mechanisms underlying its effect. In this study, IL‑8 was shown to be significantly upregulated in prostate cancer compared with paired normal control tissues. The data showed that IL‑8 exhibits direct oncogenicity, which significantly induced cell proliferation, invasion and attenuated apoptosis in prostate cancer cells via signal transducer and activator of transcription 3/protein kinase B/nuclear factor‑κB signaling pathways. In conclusion, modulation of IL‑8 expression or its associated signaling pathway may provide a novel working mechanism of IL‑8 in prostate cancer, and a promising strategy for controlling the progression and metastasis of prostate cancer.

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“…SET overexpression and involvement in tumourigenesis has been described in many cancers, including lung, prostate, ovarian and head and neck cancers, and leukaemias (Carlson et al, 1998;Neviani et al, 2005;Christensen et al, 2011;Switzer et al, 2011;Cristobal et al, 2012Cristobal et al, , 2015Cristobal et al, , 2017Agarwal et al, 2014;Gonzalez-Alonso et al, 2015;Liu et al, 2015). SET is the primary and most potent physiological inhibitor of PP2A, (Switzer et al, 2011;Neviani & Perrotti, 2014) a major mammalian serine/threonine phosphatase that plays a critical regulatory role in the cell cycle, apoptosis and appropriate deactivation of oncogenic signalling.…”

Section: Discussionmentioning

confidence: 99%

SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

et al. 2018

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Summary Alteration in RNA splicing is implicated in carcinogenesis and progression. Mutations in spliceosome genes and alternative splicing of other genes have been noted in chronic lymphocytic leukaemia (CLL), a common B cell malignancy with heterogeneous outcomes. We previously demonstrated that differences in the amount of SET oncoprotein (a physiological inhibitor of the serine/threonine phosphatase, PP2A) is associated with clinical aggressiveness in patients with CLL. It is unknown if alternative splicing of gene transcripts regulating kinases and phosphatases affects disease pathobiology and CLL progression. We show here for the first time that mRNA levels of the alternatively spliced SET isoforms, SETA and SETB (SETα and SETβ), significantly correlate with disease severity (overall survival and time‐to‐first‐treatment) in CLL patients. In addition, we demonstrate that relative increase of SETA to SETB mRNA can discriminate patients with a more aggressive disease course within the otherwise favourable CLL risk classifications of IGHV mutated and favourable hierarchical fluorescence in situ hybridisation groups. We validate our finding by showing comparable relationships of SET mRNA with disease outcomes using samples from an independent CLL cohort from a separate institution. These findings indicate that alternative splicing of SET, and potentially other signalling cascade molecules, influences CLL biology and patient outcomes.

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PP2A inhibition as a novel therapeutic target in castration-resistant prostate cancer

Cited by 14 publications

References 14 publications

Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells

Genistein targets the cancerous inhibitor of PP2A to induce growth inhibition and apoptosis in breast cancer cells

IL-8 promotes proliferation and inhibition of apoptosis via STAT3/AKT/NF-κB pathway in prostate cancer

SET alpha and SET beta mRNA isoforms in chronic lymphocytic leukaemia

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