Functional Role and Therapeutic Potential of the Pim-1 Kinase in Colon Carcinoma

Weirauch, Ulrike; Beckmann, Nadine; Thomas, Maren; Grünweller, Arnold; Huber, Kilian; Bracher, Franz; Hartmann, Roland K.; Aigner, Achim

doi:10.1593/neo.13172

Cited by 85 publications

(57 citation statements)

References 46 publications

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“…This includes the downregulation of Cyclins B1 and D1 (deceleration of cell cycle in the transition from G2 to M and from G1 to S, respectively), the activation of caspase-3/-7 (induction of apoptosis) and the decrease in the pro-survival protein Survivin. The latter finding supports our previous studies in colon carcinoma [39, 43] suggesting a SATB1 – Pim1 – Survivin axis that leads to a parallel Survivin decrease upon SATB1 knockdown. However, we found Pim1 protein levels being even elevated instead.…”

Section: Discussionsupporting

confidence: 92%

Analysis of cellular and molecular antitumor effects upon inhibition of SATB1 in glioblastoma cells

et al. 2017

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BackgroundThe Special AT-rich Sequence Binding Protein 1 (SATB1) regulates the expression of many genes by acting as a global chromatin organizer. While in many tumor entities SATB1 overexpression has been observed and connected to pro-tumorigenic processes, somewhat contradictory evidence exists in brain tumors with regard to SATB1 overexpression in glioblastoma and its association with poorer prognosis and tumor progression. On the functional side, initial data indicate that SATB1 may be involved in several tumor cell-relevant processes.MethodsFor the detailed analysis of the functional relevance and possible therapeutic potential of SATB1 inhibition, we employ transient siRNA-mediated knockdown and comprehensively analyze the cellular and molecular role of SATB1 in glioblastoma.ResultsIn various cell lines with different SATB1 expression levels, a SATB1 gene dose-dependent inhibition of anchorage-dependent and –independent proliferation is observed. This is due to cell cycle-inhibitory and pro-apoptotic effects of SATB1 knockdown. Molecular analyses reveal SATB1 knockdown effects on multiple important (proto-) oncogenes, including Myc, Bcl-2, Pim-1, EGFR, β-catenin and Survivin. Molecules involved in cell cycle, EMT and cell adhesion are affected as well. The putative therapeutic relevance of SATB1 inhibition is further supported in an in vivo tumor xenograft mouse model, where the treatment with polymeric nanoparticles containing SATB1-specific siRNAs exerts antitumor effects.ConclusionOur results demonstrate that SATB1 may represent a promising target molecule in glioblastoma therapy whose inhibition or knockdown affects multiple crucial pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3006-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Analysis of cellular and molecular antitumor effects upon inhibition of SATB1 in glioblastoma cells

et al. 2017

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“…3,18,24,30,32 Other genes affected include Pim-1, which we recently demonstrated to be functionally relevant in colon carcinoma and to play a pivotal role in several signaling pathways. 33 Here, SATB1 knockdown led to a 50% reduction in Pim-1, and we have shown previously that this leads to major changes in oncogenic signal transduction with regard to p21 Cip1/WAF1 , STAT3, JNK, c-Myc and survivin, and in the levels of apoptosis-related proteins Puma, Bax and Bcl-xL. 33 Thus, oncogenic SATB1 effects may also be mediated through Pim-1 and go all the way down to survivin, which is highly expressed in various tumor entities including colon carcinoma and is associated with elevated cell survival and proliferation, higher tumor grade, poor prognosis as well as resistance to chemotherapy and radiation (for review, see Ref.…”

Section: Discussionmentioning

confidence: 99%

Multiple effects of the special AT‐rich binding protein 1 (SATB1) in colon carcinoma

Frömberg

Rabe

Aigner

2014

Intl Journal of Cancer

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SATB1 (special AT-rich binding protein 1) is a global chromatin organizer regulating the expression of a large number of genes. Overexpression has been found in various solid tumors and positively correlated with prognostic and clinicopathological properties. In colorectal cancer (CRC), SATB1 overexpression and its correlation with poor differentiation, invasive depth, TNM (tumor, nodes, metastases) stage and prognosis have been demonstrated. However, more detailed studies on the SATB1 functions in CRC are warranted. In this article, we comprehensively analyze the cellular and molecular role of SATB1 in CRC cell lines with different SATB1 expression levels by using RNAi-mediated knockdown. Using siRNAs with different knockdown efficacies, we demonstrate antiproliferative, cell cycle-inhibitory and proapoptotic effects of SATB1 knockdown in a SATB1 gene dose-dependent manner. Tumor growth inhibition is confirmed in vivo in a subcutaneous tumor xenograft mouse model using stable knockdown cells. The in-depth analysis of cellular effects reveals increased activities of caspases-3, -7, -8, -9 and other mediators of apoptotic pathways. Similarly, the analysis of E-and N-cadherin, slug, twist, b-catenin and MMP7 indicates SATB1 effects on epithelial-mesenchymal transition (EMT) and matrix breakdown. Our results also establish SATB1 effects on receptor tyrosine kinases and (proto-)oncogenes such as HER receptors and Pim-1. Taken together, this suggests a more complex molecular interplay between tumor-promoting and possible inhibitory effects in CRC by affecting multiple pathways and molecules involved in proliferation, cell cycle, EMT, invasion and cell survival.Colorectal cancer (CRC) is one of the most common causes for cancer-related deaths in the Western world. 1 Although methods of diagnosis and treatment have improved over the last few decades, the tumor stage at diagnosis is still most important for prognosis, and the overall survival of patients with advanced CRC is still poor owing to the high risk of metastasis. 2 The special AT-rich binding protein 1 (SATB1) is a global chromatin organizer that regulates the expression of a large number of genes. 3 SATB1 interacts with the altered sugarphosphate backbone of the DNA that is specific for doublestranded base-unpairing regions (BURs). BURs are often found in matrix attachment regions (MARs) at the base of chromatin loops. 4 In the nuclei of thymocytes, SATB1 has a cage-like network distribution and tethers specialized DNA sequences onto its network. 5 Furthermore, SATB1 targets chromatin remodeling complexes to DNA at the base of chromatin loops, functioning as a "landing platform" for chromatin remodeling enzymes. 6 In this way, SATB1 folds chromatin into loops and regulates the expression of a multitude of genes in cell type-and cell function-specific manners. 5,7-10 Under physiological conditions, SATB1 is required for the development of thymocytes 8 and the activation of Th2 cells. 7 Furthermore, SATB1 participates in Xchromosome inactivation, 11 development...

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“…PIM1 phosphorylation has also been linked to the development of chemoresistance in hypoxic conditions via regulation of the mitochondrial transmembrane potential in pancreatic, cervical and colon cancer cells (38, 39). Inhibition of PIM kinases in prostate, breast and colon cancer decreases tumor cell proliferation while increasing apoptosis (40, 41). Interestingly, PIM kinases have not previously been implicated in MPNST pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial Therapy With Tamoxifen and Trifluoperazine Effectively Inhibits Malignant Peripheral Nerve Sheath Tumor Growth by Targeting Complementary Signaling Cascades

Brosius

Turk

Byer

et al. 2014

J Neuropathol Exp Neurol

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Chemotherapeutic agents effective against malignant peripheral nerve sheath tumors (MPNSTs) are urgently needed. We recently found that tamoxifen potently impedes xenograft growth. In vitro, tamoxifen inhibits MPNST proliferation and survival in an estrogen receptor-independent manner; these effects are phenocopied by the calmodulin inhibitor trifluoperazine. The present study was performed to establish the mechanism of action of tamoxifen in vivo and optimize its therapeutic effectiveness. To determine if tamoxifen has estrogen receptor-dependent effects in vivo, we grafted MPNST cells in castrated and ovariectomized mice; xenograft growth was unaffected by reductions in sex hormones. To establish whether tamoxifen and trifluoperazine additively or synergistically impede MPNST growth, mice xenografted with NF1-associated or sporadic MPNST cells were treated with tamoxifen, trifluoperazine, or both drugs for 30 days. Both monotherapies inhibited graft growth by 50%, whereas combinatorial treatment maximally reduced graft mass by 90% and enhanced decreases in proliferation and survival. Kinomic analyses showed that tamoxifen and trifluoperazine have both shared and distinct targets in MPNSTs. Additionally, trifluoperazine prevented tamoxifen-induced increases in serum/glucocorticoid regulated kinase 1, a protein linked to tamoxifen resistance. These findings suggest that combinatorial therapy with tamoxifen and trifluoperazine is effective against MPNSTs because these agents target complementary pathways that are essential for MPNST pathogenesis.

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Functional Role and Therapeutic Potential of the Pim-1 Kinase in Colon Carcinoma

Cited by 85 publications

References 46 publications

Analysis of cellular and molecular antitumor effects upon inhibition of SATB1 in glioblastoma cells

Analysis of cellular and molecular antitumor effects upon inhibition of SATB1 in glioblastoma cells

Multiple effects of the special AT‐rich binding protein 1 (SATB1) in colon carcinoma

Combinatorial Therapy With Tamoxifen and Trifluoperazine Effectively Inhibits Malignant Peripheral Nerve Sheath Tumor Growth by Targeting Complementary Signaling Cascades

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