Topic Highlight Open Access
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2014; 20(28): 9392-9404
Published online Jul 28, 2014. doi: 10.3748/wjg.v20.i28.9392
Pathophysiological roles of Pim-3 kinase in pancreatic cancer development and progression
Ying-Yi Li, Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai 200433, China
Ying-Yi Li, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200433, China
Ying-Yi Li, Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
Naofumi Mukaida, Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan
Author contributions: Li YY contributed to manuscript writing and final revision of the article; Mukaida N contributed to overall design, manuscript writing, and final revision of the article.
Supported by The National Science Foundation of China (in part), No. 30973476 and No. 812727
Correspondence to: Naofumi Mukaida, MD, PhD, Professor, Division of Molecular Bioregulation, Cancer Microenvironment Research Program, Cancer Research Institute, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. mukaida@staff.kanazawa-u.ac.jp
Telephone: +81-76-2646735 Fax: +81-76-2344520
Received: October 25, 2013
Revised: January 22, 2014
Accepted: March 8, 2014
Published online: July 28, 2014

Abstract

Pim-3 is a member of the provirus integration site for Moloney murine leukemia virus (Pim) family proteins that exhibit serine/threonine kinase activity. Similar to the other Pim kinases (Pim-1 and Pim-2), Pim-3 is involved in many cellular processes, including cell proliferation, survival, and protein synthesis. Although Pim-3 is expressed in normal vital organs, it is overexpressed particularly in tumor tissues of endoderm-derived organs, including the liver, pancreas, and colon. Silencing of Pim-3 expression can retard in vitro cell proliferation of hepatocellular, pancreatic, and colon carcinoma cell lines by promoting cell apoptosis. Pim-3 lacks the regulatory domains similarly as Pim-1 and Pim-2 lack, and therefore, Pim-3 can exhibit its kinase activity once it is expressed. Pim-3 expression is regulated at transcriptional and post-transcriptional levels by transcription factors (e.g., Ets-1) and post-translational modifiers (e.g., translationally-controlled tumor protein), respectively. Pim-3 could promote growth and angiogenesis of human pancreatic cancer cells in vivo in an orthotopic nude mouse model. Furthermore, a Pim-3 kinase inhibitor inhibited cell proliferation when human pancreatic cancer cells were injected into nude mice, without inducing any major adverse effects. Thus, Pim-3 kinase may serve as a novel molecular target for developing targeting drugs against pancreatic and other types of cancer.

Key Words: Serine/threonine kinase, Pancreatic cancer, Ets-1, Translationally controlled tumor protein, c-Myc, Vascular endothelium growth factor, Apoptosis, Cell cycle

Core tip: The present review describes the current knowledge on the roles of Pim-3 in pancreatic cancer development and progression, and provides the possibility for Pim-3 as a therapeutic target in human pancreatic cancer.



INTRODUCTION

Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States[1]. Patients usually suffer from non-specific abdominal discomfort in the primary stages, which often delay early diagnosis and treatment. Furthermore, even in the initial evolutionary phase of disease development, pancreatic cancer cells tend to undergo invasion and metastasis. Therefore, complete removal of tumors by surgical procedures is often impossible. Another major stumbling block in treating pancreatic cancer is its frequent resistance to chemotherapy and radiotherapy treatment. Consequently, pancreatic cancer has an exceptionally poor prognosis, with an overall 5-year survival rate of less than 5%[2,3]. Thus, a novel molecular targeted therapy will be a required therapeutic option for human pancreatic cancer treatment.

Malignant lesions of the pancreas show a ductal, acinar, or endocrine lineage. Nearly 80% of pancreatic carcinomas are classified as pancreatic ductal adenocarcinoma (PDAC)[4]. An activating mutation in a key proto-oncogene has been observed in most PDACs, and is presumed to be the first significant event involved in pancreatic carcinogenesis[4]. The development and progression of PDAC is associated with additional multiple genetic and epigenetic alterations in several proto-oncogenes, tumor-suppressor genes, and signaling pathways. Pim-3 kinase has essential roles in the regulation of signal transduction cascades. Moreover, its expression is enhanced in human pancreatic cancer cell lines, and blocking of its expression induced apoptosis and decreased chemoresistance in human pancreatic cancer[5,6].

The provirus integration site for the Moloney murine leukemia virus (Pim) family is a proto-oncogene, which belongs to the calcium/calmodulin-regulated kinase group and exhibits serine/threonine kinase activity[7]. The Pim family consists of three members: Pim-1, Pim-2, and Pim-3[8]. The Pim-1 gene was first discovered as a proviral insertion site in Moloney murine leukemia virus[9]. A subsequent study demonstrated that Pim-1 transgenic mice are predisposed to the development of experimental T cell lymphoma in cooperation with c-Myc and N-Myc[10]. Pim-2 was similarly identified as a proviral integration site in Moloney murine leukemia virus-induced T cell lymphomas[11], and can synergize with c-Myc-induced lymphomagenesis[8]. Pim-3 was first identified as a novel gene induced by membrane depolarization or forskolin in rat PC12 pheochromocytoma cells, and was designated as kinase induced by depolarization (KID-1)[12]. Subsequently, KID-1 was renamed Pim-3 due to its high sequence similarity with the other Pim family proteins Pim-1 and Pim-2. Although Pim-3 can be detected in several normal tissues, including those of the brain and heart, it is expressed in high levels in tumor tissues of various organs, particularly those of endoderm-derived organs such as the pancreas, liver, colon, and stomach[5,13,14].

In this review, we aim to highlight the pathophysiological roles of Pim-3 in the development and progression of cancer, particularly pancreatic cancer. Moreover, by considering the sequence similarity of Pim-3 with other Pim kinases, we were able to rationalize and predict the possible functions of Pim-3 by extrapolating from the data established for other Pim family members, particularly Pim-1. We further discuss the potential of Pim-3 as a novel molecular target for antineoplastic therapy.

STRUCTURE OF PIM-3 PROTEIN

The open reading frame of human Pim-3 mRNA encodes a protein consisting of 326 amino acids with a calculated molecular weight of 35861 (Figure 1)[13]. Human Pim-3 protein shares a high percentage of sequence homology with other members of the Pim family; Pim-3 and Pim-1 are 71% identical at the amino acid level, and Pim-3 and Pim-2 are 44.0% identical[14-17].

Figure 1
Figure 1 Amino acid alignment of human Pim family proteins[13]. The amino acid sequences of human Pim family kinases are aligned and common residues shared with Pim-3 are highlighted. The box indicates the hinge region. Residues marked with white and red are important for adenosine triphosphate binding and substrate selectivity, respectively.

The crystal structure of the Pim-3 protein has not yet been established, but several research groups have independently reported the crystal structure of Pim-1 and Pim-2 in the free form, as well as in complex with their inhibitors[18-22]. The Pim-1 kinase adopts a two-lobe kinase fold connected by a hinge region (residues 121-126)[18]. The N-terminal lobe is composed of antiparallel β-sheets, while the C-terminal lobe is composed mainly of α-helices (Figure 1). The adenosine triphosphate (ATP)-binding site is located in a deep intervening cleft between the two lobes and the hinge region. The Pim family proteins have no regulatory domains. Moreover, the ATP binding pocket in Pim-1 remains open irrespective of the presence or absence of ATP[18], indicating a continuous maintenance of an active state conformation. Similar findings have been reported for the structure of Pim-2 kinase[20]. This may account for the good correlation between protein expression levels and overall kinase activity in the case of Pim-1 and Pim-2[15]. Given the high sequence similarity (Figure 1 and NCBI Reference Sequence: NP_001001852.2), it is highly likely that Pim-3 kinase can adopt a similar three dimensional active conformation. Importantly, several residues believed to confer specificity in Pim-1 kinase are also conserved within Pim-2 and Pim-3 proteins.

MECHANISMS UNDERLYING CONTROL OF PIM-3 EXPRESSION

Pim-3 mRNA is detected in several normal human tissues, including the heart, brain, lung, kidney, spleen, placenta, skeletal muscle, and peripheral blood leukocytes, but not in the colon, thymus, liver, or small intestine[13]. Pim-3 is expressed in endothelial cells[23]. Focal cerebral ischemia enhances Pim-3 mRNA expression in the peri-infarction cortex at early time points[24]. Similarly, ischemia reperfusion injury enhances intra-cardiac Pim-3 expression through the p38-mediated signaling pathway[25]. In the mouse embryo, Pim-3 gene expression is detected in the liver, kidneys, lungs, thymus, central nervous system, periphery of the pancreas, secretory epithelium of the stomach, and intestinal epithelium[26].

Pim-3 mRNA is found to be expressed in a panel of human Ewing’s family tumor cell lines[27] and nasopharyngeal carcinoma cell lines[28]. Likewise, we revealed that Pim-3 protein is scarcely detected in adult normal endoderm-derived organs, such as the liver, pancreas, colon, and stomach, but its expression is augmented in premalignant and malignant lesions of these organs (Table 1)[5,13,29,30]. Pim-3 protein is mostly detected in the cytoplasm of these tumors. In the liver, aberrant expression of Pim-3 protein is also observed in precancerous lesions such as regenerative nodules and adenomatous hyperplasia[13]. Similarly, in the colon and stomach, Pim-3 protein is detected at higher levels in adenoma tissues compared with adenocarcinoma tissues[29,30]. These observations suggest that Pim-3 plays a crucial role in the initial phase of carcinogenesis.

Table 1 Increased expression patterns for Pim kinases in various types of malignancies.
Tumor subtypePim-1Pim-2Pim-3
Solid tumor
Pancreatic cancer+ND+
Colon carcinoma+ND+
Gastric cancer+ND+
Hepatocellular carcinoma+++
Prostate adenocarcinoma+++
Bladder carcinoma+NDND
Squamous cell carcinoma of head and neck+NDND
Nasopharyngeal carcinomaNDND+
Oral squamous cell carcinoma+NDND
Liposarcoma+NDND
Ewing’s sarcomaNDND+
Hematological malignancies
Acute myeloid leukemiaND+ND
B Cell chronic lymphocytic leukemiaND+ND
Primary mediastinal large B cell lymphoma+NDND
Mantle cell lymphoma++ND
Diffuse large B cell lymphoma++ND
Burkitt’s lymphoma+NDND

Pim-3 expression is regulated mainly at transcriptional and post-transcriptional levels. We will discuss the regulatory mechanisms of these two levels in detail.

Transcriptional regulation of Pim-3 expression

Ewing’s sarcoma (EWS)./Ets fusion proteins are pathognomonic for EWS. These fusion proteins arise from the chromosomal translocations that combine a portion of the amino-terminal region of EWS to one of the five members of Ets family transcription factors: friend leukemia integration transcription factor (FLI), Ets-related gene (ERG), FEV, Ets translocation variant 1, or Ets translocation variant 4[31]. Deneen et al[27] demonstrated that EWS/Ets fusion proteins can enhance Pim-3 gene transcription in NIH 3T3 cells.

We have determined the 5′-flanking region of the human Pim-3 gene as that necessary in order to elucidate the molecular mechanisms underlying constitutive Pim-3 expression in human pancreatic cancer cells. The human Pim-3 gene contains a canonical TATA box and putative binding sites for several known transcription factors, such as signal transducer and activator of transcription (Stat)3, Sp1, and Ets-1, as well as nuclear factors NF-κB and NF-1[32]. Pim-3 expression is enhanced in murine embryonic stem cells by leukemia inhibitory factor (LIF)/gp130-dependent signaling and the Stat3 transcription factor[33]. In contrast, the transfection of the dominant negative form of Stat3 failed to inhibit the promoter activity of the Pim-3 gene in human pancreatic cancer cells[32]. We further demonstrated that the region between -264 and -164 bp is essential for constitutive Pim-3 gene expression. This region contains one NF-κB, two Sp1, and two Ets-1 binding sites. Pim-1 gene can be induced by CD40-mediated signaling in an NF-κB-dependent manner[34]. However, mutation in the NF-κB binding site of the Pim-3 gene failed to reduce promoter activities in human pancreatic cancer cells[32]. Further examination has revealed that the two Sp1 binding sites and the distal Ets binding site are crucial for constitutive Pim-3 gene expression in human pancreatic cancer cells. The crucial roles of Ets-1 in constitutive Pim-3 gene expression are further supported by our observations that the overexpression of Ets-1 enhances Pim-3 expression, whereas the transfection of the dominant negative form of Ets-1 or Ets-1 small interfering RNA (siRNA) reduces Pim-3 expression in human pancreatic cancer cells[32]. As the expression of both Ets-1 and Sp1 is enhanced in various types of cancer, including pancreatic cancer[35,36], Ets-1 and Sp1 may act cooperatively to induce constitutive Pim-3 gene expression as observed with their other target genes[37].

Post-transcriptional regulation of Pim-3 expression

Pim kinase mRNAs have multiple copies of AUUUA sequences in their 3′ untranslated regions (UTR); a typical characteristic sequence of mRNA with a short half-life. GC-rich sequences are present in the 5′ UTR of Pim mRNAs and frequently require cap-dependent translation. Indeed, the overexpression of eukaryotic translation initiation factor 4E (eIF4E) leads to an increase in Pim-1 protein levels, indicating that Pim-1 mRNA is translated in a cap-dependent manner[38]. Moreover, the eukaryotic translation initiation factor eIF4E can bind a stem-loop-pair sequence present in the 3′ UTR of Pim-1 mRNA, which allows nuclear export and translation of Pim-1 transcript[39]. Since Pim-3 mRNA shows analogous sequences as Pim-1 mRNA, the translation of Pim-3 mRNA can be regulated in a similar way.

Similar to Pim-1, Pim-3 can autophosphorylate some of its serine residues, but whether this has any functional significance is yet to be determined[19]. Moreover, Pim-1 and Pim-3 have been shown to bind to the serine/threonine protein phosphatase 2A (PP2A), resulting in their dephosphorylation, ubiquitination, and proteasomal degradation[40,41].

3′UTR of Pim-1 harbors multiple binding sites for miRNAs, including miRNA-33[42], miRNA-16[43], miRNA-1[44], miRNA-328[45], and miRNA-210[46]. miRNAs are generally highly conserved evolutionarily[42]. They can bind to the putative target sites present in the 3′UTR of the Pim-1 gene and directly inhibit its expression at the post-transcriptional level, thereby blocking proliferation and growth of cancer and smooth muscle cells. The relevant analysis for the structure of human Pim-3 mRNA indicates that the 3’UTR of the Pim-3 gene harbors multiple binding sites for miRNAs (http://www.ebi.ac.uk; http://www.microrna.org). It will be interesting to know whether Pim-3 translation can be regulated in a similar manner.

We have identified a translationally controlled tumor protein (TCTP/TPT1) that interacts with Pim-3 by using yeast two-hybrid screening[47]. TCTP was aberrantly expressed and co-localized with Pim-3 in human pancreatic cancer cells. Mapping studies have confirmed that this co-localization is due to the interaction between the amino acids in the C-terminal fold of Pim-3 and the amino acids in the N-terminal sequence of TCTP. Pim-3 had no effect on TCTP expression or phosphorylation, although overexpression of TCTP increased Pim-3 expression in a dose-dependent manner. RNAi-mediated ablation of TCTP expression reduced Pim-3 protein, but not mRNA via the ubiquitin-proteasome degradation pathway. The resultant reduced Pim-3 expression eventually inhibited tumor growth in vitro and in vivo by arresting cell cycle progression and enhancing apoptosis. Furthermore, TCTP and Pim-3 expression were significantly correlated in pancreatic adenocarcinoma specimens and in tumors from patients showing high expression levels of TCTP and Pim-3 obtained at an advanced stage of cancer. Thus, TCTP-mediated enhancement of Pim-3 protein expression may be involved in the regulation of cell cycle progression and apoptosis in pancreatic carcinogenesis[47].

BIOLOGICAL FUNCTIONS OF PIM-3

Treatment with Pim-3 shRNA can decrease in vitro proliferation of various types of cancer cells by inducing apoptosis[5,13,29]. The major function of BAD (Bcl-2-associated death promoter), a pro-apoptotic BH3-only protein, is to regulate apoptosis. Unphosphorylated BAD binds and eventually inactivates anti-apoptotic family members, primarily Bcl-XL, but also Bcl-2. Phosphorylation of BAD at Ser112, Ser136, and Ser155 impairs its binding to Bcl-XL and Bc1-2, and the translocation of BAD from the surface of mitochondria to the cytosol is guided by the protein 14-3-3. The presence of unbound Bc1-XL maintains mitochondrial membrane potential and inhibits apoptosis[48,49]. Pim-1 and Pim-2 can phosphorylate BAD at Ser112, while Akt phosphorylates Ser136 and Ser155. The phosphorylation of BAD can result in its inactivation, leading to the subsequent inhibition of apoptosis[50,51]. Elevated levels of Pim-3 increases the amount of BAD phosphorylated at Ser112 and inhibits apoptosis, while Pim-3 shRNA treatment dephosphorylates Ser112 and promotes apoptosis (Figure 2)[5,29]. Therefore, similar to Akt and other Pim kinases, Pim-3 can modulate apoptosis by phosphorylating the pro-apoptotic molecule, BAD. Moreover, Pim-3 gene transduction increased Bcl-2 expression, suppressed apoptosis (as evidenced by reduced caspase-3 activation), and eventually protected against hepatic failure in D-galactosamine-sensitized rats receiving lipopolysaccharide[52]. Similarly, the transfection of the Pim-3 gene into cardiomyocytes attenuated ischemia/reperfusion injury-induced cell death through a p38 mediated MAPK signaling pathway[25]. Erythropoietin can protect renal cells from apoptosis by activating Stat5, and this anti-apoptotic effect is also mediated by Pim-3[53].

Figure 2
Figure 2 Presumed biological functions of Pim-3. Pim-3 can interact with various target molecules, and thereby regulates various biological pathways including apoptosis, cell cycle, protein synthesis, and transcription.

Pim-3 shows a high sequence identity with Pim-1, even at their kinase domains (Figure 1). Both Pim-1 and Pim-3 bind to a consensus peptide substrate (AKRRRRHPSGPPTA) with a remarkable high affinity (Kd = 40-60 nmol/L), whereas the binding affinity of this peptide for Pim-2 is relatively weak (640 nmol/L)[19]. Therefore, Pim-1 and Pim-3 can phosphorylate the same or a similar set of substrates, and the evaluation of Pim-1 characteristics and functions can provide useful insights into deciphering the major biological functions of Pim-3. In addition to BAD, Pim kinases can phosphorylate a wide range of cellular proteins. These include transcription factors (Stat[54], c-Myc[55], Myb[56], and runt-related transcription factors RUNX1 and RUNX3), cell cycle regulators (p21CIP, p27KIP1, Cdc25A, and Cdc25C), signaling pathway intermediates (suppressor of cytokine signaling 1 (SOCS1)[57], SOCS3[58], and MAP3K5[59]), and regulators of protein synthesis (eukaryotic translation initiation factor 4B (eIF4B))[60].

Pim-1 can phosphorylate Cdc25A, thereby increasing its phosphatase activity and the activity of cyclin D1-associated kinases, which can result in cell cycle progression[61]. Pim-1 phosphorylates Cdc25C-associated kinase 1 (C-TAK1), which can potently inhibit Cdc25C and promote cell cycle progression at the G2/M phase[62]. Pim-1 can phosphorylate the threonine residue of p21, another molecule involved in cell cycle progression. Its phosphorylation leads to its relocation to the cytoplasm, resulting in enhanced protein stability and eventually leading to increased cell proliferation[63,64]. All Pim kinases, including Pim-3, can phosphorylate CDK inhibitor p27 at its threonine residues, thereby inducing the binding of p27 to 14-3-3 protein, resulting in its nuclear export and proteasome-dependent degradation[65]. Moreover, Pim-1 phosphorylates and inactivates forkhead transcription factors FoxO1a and FoxO3a, resulting in depressed p27 gene transcription, which leads to cell cycle progression (Figure 2)[65]. Similarly, transfection with Pim-3 shRNA reduced the G1 population of human pancreatic cancer cells compared with the cells transfected with scramble shRNA[5]. Moreover, a small-molecule Pim-3 kinase inhibitor markedly retarded in vitro growth of human pancreatic cancer cell lines by inducing G2/M arrest[66], suggesting a potential role for Pim-3 in cell cycle progression. Cell cycle progression is consistently accelerated in hepatocytes of transgenic mice, which express human Pim-3 cDNA selectively in hepatocytes[67], and downregulation of Pim-3 decreased the amounts of Cdc25C, cyclin B1, and phospho-p21 (our unpublished data). Thus, Pim-3 can promote cell cycle progression and eventually contribute to carcinogenesis by modulating the functions of these regulatory molecules involved in cell cycle progression.

Mice deficient in all three Pim kinases are designated as triple knockout (TKO) mice. TKO mice have reduced body size at birth and throughout the postnatal period of their life, but are viable and fertile[68]. However, TKO mouse-derived embryonic fibroblasts (MEFs) show depressed AMP-dependent protein kinase (AMPK) activity, grow slowly in culture medium, and have decreased rates of 5′-cap-dependent protein synthesis[69]. Transduction of the Pim-3 gene alone into these MEFs can reverse AMPK activation, increase protein synthesis, and drive the growth to a similar level as wild-type MEFs. Moreover, Pim-3 expression can markedly increase the levels of c-Myc and the peroxisome proliferation-activated receptor γ co-activator 1α (PGC-1α), enzymes capable of regulating glycolysis, and mitochondrial biogenesis[69]. Similarly, Pim-1 and Pim-2 phosphorylate serine and threonine residues of c-Myc protein[55]. Furthermore, Pim-1 can act as a co-activator of Myc by phosphorylating Ser10 of histone H3 on the nucleosome at the Myc-binding sites[70]. Thus, Pim-3 can augment the rate of protein synthesis by modulating AMPK, c-Myc, and PGC-1α (Figure 2).

Pim-1 and Pim-3 together play a significant role in maintaining the self-renewal capacity of mouse embryonic stem (ES) cells in vitro[33]. ES cells overexpressing Pim-1 and Pim-3 have a greater capacity to self-renew and display a greater resistance to LIF deprivation, as evidenced by a clonal assay. On the other hand, ablation of Pim-1 and Pim-3 genes increases the rate of spontaneous differentiation in a self-renewal assay, and impairs the growth of undifferentiated ES cell colonies with increased rate of apoptosis[33].

Pim-3 is highly expressed at the cellular lamellipodia in endothelial cells, and is co-localized with focal adhesion kinase (FAK). In addition, Pim-3 shRNA treatment impairs endothelial cell spreading, migration, and proliferation, leading to a reduction in tube-like structure development in a Matrigel assay[23]. However, TKO mice did not display any apparent abnormal phenotypes in embryogenesis or vascular development[68].

Pim-3 expression is detected in the β cells located in the pancreatic islets[71]. Pim-3-deficient mice exhibit an increased glucose tolerance and insulin sensitivity. Moreover, Pim-3 can negatively regulate insulin secretion by inhibiting the activation of Erk1/2 via SOCS6[71]. In contrast, the inhibition of another survival kinase, Akt, can induce hyperglycemia[72,73].

The switch from the latent phase to productive viral reactivation (lytic phase) is crucial for sustaining viral multiplication in infected host cells. Findings from a recent clinico-epidemiological study indicated the importance of lytic reactivation in the development and progression of Kaposi’s sarcoma (KS)[74]. Latency-associated nuclear antigen (LANA) is presumed to be a novel regulator of the life cycle of γ herpes virus, including Kaposi’s sarcoma herpes virus (KSHV). Pim-1 and Pim-3 contribute to the viral reactivation of KSHV by phosphorylating LANA, and thereby promote KS progression[74].

ROLES OF PIM-3 IN CANCER DEVELOPMENT AND PROGRESSION, PARTICULARLY IN THE PANCREAS

Pim-3 can contribute to cancer development and progression by acting on tumor cells and microenvironments. The primary activities of Pim-3 on tumor cells include the delivery of survival signaling, the regulation of cell cycle progression, protein synthesis, and Myc activation (Figure 3). In addition to its effects on tumor cells, Pim-3 can have profound impacts on tumor microenvironments, especially the neovascularization process (Figure 3). In the following sections we will discuss the roles of Pim-3 in carcinogenesis, with a focus on these two aspects.

Figure 3
Figure 3 Presumed roles of Pim-3 in pancreatic carcinogenesis. Pim-3 expression is regulated at transcriptional and post-transcriptional levels by transcription factors (such as Ets-1) and post-translational controllers (such as translationally controlled tumor protein), respectively. Pim-3 kinase activation contributes to pancreatic carcinogenesis by inducing cell survival, cell cycle progression, gene transcription, protein synthesis in tumor cells, and angiogenesis.
Effects of Pim-3 on tumor cells

Forced expression of Pim-3 can promote anchorage-independent growth, whereas co-expression of a kinase-dead Pim-3 mutant can attenuate EWS/FLI-mediated NIH 3T3 tumorigenesis in immunodeficient mice[27]. These observations suggest the involvement of Pim-3 in cancer development and progression.

Pim-3 can prevent apoptosis in pancreatic cancer cells by phosphorylating BAD, a pro-apoptotic molecule on the serine residues (Ser112, Ser136, or Ser155), which in turn prevents Bcl-XL binding and promotes BAD translocation from the surface of the mitochondria to the cytosol via the protein 14-3-3[48,49]. Among the serine residues present in BAD, Ser112, but not Ser136 and Ser155, is abundantly phosphorylated in human pancreatic cancer cell lines. Moreover, the ablation of endogenous Pim-3 reduces the population of phosphorylated BAD, followed by an enhancement of apoptosis, whereas Pim-3 overexpression produces exactly the opposite phenotypes. These observations suggest that Pim-3 has a crucial role in preventing apoptosis of human pancreatic cancer cells.

Cell survival can be regulated by Wnt/β-catenin and Stat3 signaling pathways. An integrative molecular screening using siRNA identified Pim-3 as a new regulator of Wnt/β-catenin signaling[75]. Thus, Pim-3 can positively regulate the Wnt/β-catenin signaling pathway in the colorectal cancer cell lines (DLD-1 and SW480)[75]. Moreover, Pim-3 is a positive regulator of Stat3 signaling in the prostate cancer cell line (DU-145) and in the pancreatic cancer derived cell line (MiaPaCa2)[56]. Thus, Pim-3 can promote cancer cell survival by modulating Wnt/β-catenin and/or Stat3 signaling pathways.

Pm-1 can promote cell cycle progression by phosphorylating and modulating the functions of molecules involved in cell cycle progression. Moreover, Pim kinases positively regulate transcription factors controlling the expression of genes implicated in cell cycle progression[65]. Since Pim-3 shares a high sequence identity with Pim-1, it is possible that Pim-3 can perform similar regulatory functions as Pim-1. Treatment with Pim-3 shRNA showed a marked reduction in the G1 population of human pancreatic cancer cells, while scramble shRNA had few effects[5]. Furthermore, a small-molecule Pim-3 kinase inhibitor markedly retarded the in vitro growth of human pancreatic cancer cell lines by inducing G2/M arrest[66]. These findings indicate that Pim-3 may have a major influence in cell cycle progression of cancer cells.

Pim-1 and Pim-2 help in cell survival by suppressing myc-induced apoptosis[10,11]. Transgenic mice expressing (immunoglobulin heavy-chain enhancer)-Pim-1 and Eμ-Myc succumb to lymphoma in utero or around birth[76]. On the contrary, Eμ-Myc transgenic mice that are deficient in Pim-1 and Pim-2 genes develop lymphoma slowly over time[8]. Thus, Myc-driven tumorigenesis depends on physiological levels of Pim-1 and Pim-2 expression. Several mechanisms have been proposed to explain the cooperation between Myc and Pim kinases. Myc recruits Pim-1 to the E-boxes of the Myc target genes such as Fos-related antigen 1 [FOSL1 (Fra-1)], DNA-binding protein inhibitor ID2, and Pim-1 phosphorylates Ser10 of histone H3 on the nucleosome at the Myc-binding sites that acts as a co-activator of Myc[70]. An expression profile analysis demonstrated that about 20% of Myc-regulated genes are also under the control of Pim-1[70]. Moreover, Pim-1 and Pim-2 phosphorylate c-Myc protein at its serine and threonine residues[55]. This results in the stabilization and subsequent enhancement of the transcription activities of c-Myc protein. Furthermore, Pim-3 can enhance c-Myc mRNA expression through the activation of PGC-1α[69]. The enhanced expression of c-Myc and PGC-1α may account for enhanced glycolysis. Thus, Pim kinases can promote tumorigenesis by modulating the activities of c-Myc and promoting Warburg effects[10,11].

Roles of Pim-3 in tumor microenvironments

One of the basic characteristic features of tumor tissues is the abundance of newly formed vasculature for the supply of nutrients and oxygen to the growing tumor cells, as well as the elimination of metabolic wastes and carbon dioxide. Pim-3 is abundantly expressed at mRNA and protein levels at the cellular lamellipodia, and is co-localized with FAK in endothelial cells[23]. Pim-3 shRNA treatment impaired endothelial cell spreading, migration, and proliferation, leading to a reduction in tube-like structure formation in a Matrigel assay[23]. Moreover, tumor necrosis factor (TNF)-α transiently increases Pim-3 mRNA expression via the TNF receptor-1 pathway in endothelial cells (ECs), and eventually promotes EC spreading and migration[77]. Constitutive Pim-3 overexpression in gastric cancer tissues can induce angiogenesis[30].

Tumor-associated neovasculature formation is regulated by various angiogenic factors. Notably, vascular endothelial growth factor (VEGF) has an important role in tumor-associated vasculature formation[78,79]. Although most pancreatic cancer tissues are hypovascular, elevated levels of VEGF are sometimes detected in pancreatic cancer cells[80]. Earlier studies have demonstrated that Pim-3 overexpression was responsible for increased VEGF expression and the growth of pancreatic cancer in vivo in an orthotopic nude mouse model[81]. The lack of any vascular phenotypes in Pim-3-deficient mice indicates that Pim-3 is dispensable for normal vasculature formation. However, given distinctive gene expression profiles of tumor-associated ECs[82], Pim-3 may have distinct roles in tumor-associated endothelial cells.

PHARMACOLOGICAL CHARACTERIZATION OF PIM-3 INHIBITORS

It is obvious from our discussions that aberrant activation and expression of Pim kinases are associated with various types of cancer. Enhanced expression of Pim-2 kinase is detected in hematologic malignancies and prostate cancer. Additionally, increased Pim-1 expression is observed in pancreatic cancer, squamous cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma[83-85], bladder carcinoma[86], and liposarcoma[87]. In contrast, Pim-3 expression is selectively overexpressed in malignant lesions of endoderm-derived organs such as the liver[13], pancreas[5], colon[29], and stomach[30]. Furthermore, a lack of apparent phenotypes in TKO mice suggests that Pim kinases are dispensable for the maintenance of normal functions of vital organs. Collectively, Pim kinases can be good candidate molecules for targeted cancer therapy. Examples of Pim-1 inhibitors include an anti-Pim-1 antibody and a cell penetrating peptide, both of which suppresses tumor growth in vivo in xenograft mouse models transplanted with human cancer cell lines[88,89].

The crystal structure of Pim-3 has not yet been reported. However, the crystal structure of Pim-1 and Pim-2 has been resolved, which revealed the presence of a unique hinge region that connects the two lobes of the protein kinase domain[18-20]. As a result, ATP binds to Pim kinases in a fundamentally different way from how it binds to other protein kinases[18,19]. Thus it may be possible to design compounds which will selectively inhibit Pim kinases but not other serine/threonine kinases[16].

Several independent research groups have developed small-molecule inhibitors against Pim kinases, including flavonol quercetagetin[90], imidazole[1,2-b]pyridazines[91,92], benzylidene-thiazolidine-2,4-dione[93-95], 3,5-disubstituted indole derivatives[96], pyrazolo[3,4-g]quinoxaline derivatives[97], 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazole derivatives[98], and pyrrolo[2,3-a]carbazole and pyrrolo[2,3-g]indazole derivatives[99-101]. Among them, 1,6-dihydropyrazolo[4,3-c]carbazoles, 3,6-dihydropyrazolo[3,4-c]carbazoles, and pyrrolo[2,3-g]indazoles can inhibit Pim-3 activities[98,100]. In our previous studies, we have demonstrated that derivatives of stemoamide synthetic intermediates can inhibit Pim-3 as well as Pim-1 and Pim-2 activities, and can reduce tumor growth in vivo in mouse xenograft models using human pancreatic cancer cell line without causing major adverse side-effects[102,103].

The substrates preferred by Pim-1 and Pim-3[19] are very similar in identity. Therefore, designing isoform specific inhibitors that will differentiate and preferentially bind to one Pim member over the other is extremely challenging. Indeed, pyrrolo[2,3-a]carbazole has low nanomolar binding affinity for Pim-1 and Pim-3 kinases, but only weakly inhibits Pim-2 (IC50 for Pim-1, 0.57 + 0.04 μmol/L; IC50 for Pim-2, > 10 μmol/L; IC50 for Pim-3, 0.04 + 0.01 μmol/L)[104]. Similar pharmacological observations have been recorded with phenanthrene derivatives[77]. However, it will be interesting to find out if an inhibitor which specifically inhibits the action of one Pim member will provide any additional advantage over a multi-Pim kinase inhibitor.

Akt can phosphorylate a similar set of substrates to Pim kinases, such as BAD, thereby initiating the proliferation of cancer cells[105]. Akt is aberrantly activated in various types of tumors, and Akt inhibitors have been extensively investigated[72]. The Akt inhibitor “GSK690693” has exhibited potent antitumor activity in pre-clinical trials on animals[105]. Akt is a key signaling protein and Akt-2 is directly involved in the insulin receptor signaling pathway. Consequently, the genetic disruption of Akt kinase genes results in severe phenotypic changes, such as neonatal mortality, severe growth retardation, and reduced brain size[106-108], and Akt-2 inhibition induces severe hyperglycemia[105]. The use of Akt inhibitors for anti-cancer treatment is seriously limited because of these shortcomings. In contrast, Pim kinases, including Pim-3, are not involved in the insulin receptor signaling pathway, and the inhibition of Pim kinases hardly shows any detrimental effects on normal glucose metabolism. Thus, Pim kinases are more effective molecular targets than Akt for targeted cancer therapy, and are particularly useful for treating pancreatic cancer, which is frequently complicated by hyperglycemia.

CONCLUSION

Pim-3 kinase is aberrantly expressed in malignant lesions but not in normal tissues of endoderm-derived organs, such as the liver, pancreas, colon, and stomach[5,13,29,30], and contributes to tumorigenesis by inhibiting apoptosis of tumor cells and promoting cell cycle progression. Moreover, genetic deficiency of the Pim-3 gene does not result in apparent changes in phenotypes, suggesting that Pim-3 may be physiologically dispensable. Unlike Akt kinases[72], Pim kinases are not involved in the insulin receptor signaling pathway; therefore, the inhibition of Pim kinases has very little influence on glucose metabolism. Indeed, inhibition of Pim-3 kinase activities slows the growth or even causes regression of pancreatic tumors in mice without causing hypoglycemia[66,102,103]. Since Pim-3 kinase is constitutively active once it is expressed aberrantly, inhibition of Pim-3 can be used for inhibiting cancer progression. Furthermore, there is accumulating evidence to suggest that Pim-3 plays a vital role in the interaction between tumor cells and their surrounding stroma. Further studies on these aspects will unravel the novel pathophysiological role of Pim-3. Nevertheless, strategies to inhibit Pim-3 activity warrant intensive investigation in order to discover and develop new targeted anti-cancer therapeutics.

ACKNOWLEDGMENTS

We would like to express our sincere gratitude to Dr. Tomohisa Baba (Cancer Research Institute, Kanazawa University) for his critical comments on the manuscript.

Footnotes

P- Reviewer: Abbott DE, Ceyhan GO, He H, Massironi S S- Editor: Ma YJ L- Editor: Rutherford A E- Editor: Zhang DN

References
1.  Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8406]  [Cited by in F6Publishing: 8894]  [Article Influence: 741.2]  [Reference Citation Analysis (0)]
2.  Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049-1057.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1481]  [Cited by in F6Publishing: 1506]  [Article Influence: 75.3]  [Reference Citation Analysis (0)]
3.  Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10002]  [Cited by in F6Publishing: 10347]  [Article Influence: 739.1]  [Reference Citation Analysis (0)]
4.  Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378:607-620.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1720]  [Cited by in F6Publishing: 1878]  [Article Influence: 144.5]  [Reference Citation Analysis (3)]
5.  Li YY, Popivanova BK, Nagai Y, Ishikura H, Fujii C, Mukaida N. Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines. Cancer Res. 2006;66:6741-6747.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 127]  [Cited by in F6Publishing: 140]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
6.  Xu D, Cobb MG, Gavilano L, Witherspoon SM, Williams D, White CD, Taverna P, Bednarski BK, Kim HJ, Baldwin AS. Inhibition of oncogenic Pim-3 kinase modulates transformed growth and chemosensitizes pancreatic cancer cells to gemcitabine. Cancer Biol Ther. 2013;14:492-501.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 22]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
7.  Konietzko U, Kauselmann G, Scafidi J, Staubli U, Mikkers H, Berns A, Schweizer M, Waltereit R, Kuhl D. Pim kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP. EMBO J. 1999;18:3359-3369.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 69]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
8.  Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E, Berns A. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet. 2002;32:153-159.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 286]  [Cited by in F6Publishing: 309]  [Article Influence: 14.0]  [Reference Citation Analysis (0)]
9.  Cuypers HT, Selten G, Quint W, Zijlstra M, Maandag ER, Boelens W, van Wezenbeek P, Melief C, Berns A. Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell. 1984;37:141-150.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, Berns A. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989;56:673-682.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Breuer ML, Cuypers HT, Berns A. Evidence for the involvement of pim-2, a new common proviral insertion site, in progression of lymphomas. EMBO J. 1989;8:743-748.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Feldman JD, Vician L, Crispino M, Tocco G, Marcheselli VL, Bazan NG, Baudry M, Herschman HR. KID-1, a protein kinase induced by depolarization in brain. J Biol Chem. 1998;273:16535-16543.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Fujii C, Nakamoto Y, Lu P, Tsuneyama K, Popivanova BK, Kaneko S, Mukaida N. Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines. Int J Cancer. 2005;114:209-218.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 70]  [Cited by in F6Publishing: 79]  [Article Influence: 4.2]  [Reference Citation Analysis (0)]
14.  Mukaida N, Wang YY, Li YY. Roles of Pim-3, a novel survival kinase, in tumorigenesis. Cancer Sci. 2011;102:1437-1442.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 63]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
15.  Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer. 2011;11:23-34.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 360]  [Cited by in F6Publishing: 368]  [Article Influence: 28.3]  [Reference Citation Analysis (0)]
16.  Brault L, Gasser C, Bracher F, Huber K, Knapp S, Schwaller J. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010;95:1004-1015.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 252]  [Cited by in F6Publishing: 277]  [Article Influence: 19.8]  [Reference Citation Analysis (0)]
17.  Blanco-Aparicio C, Carnero A. Pim kinases in cancer: diagnostic, prognostic and treatment opportunities. Biochem Pharmacol. 2013;85:629-643.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 106]  [Cited by in F6Publishing: 122]  [Article Influence: 10.2]  [Reference Citation Analysis (0)]
18.  Qian KC, Wang L, Hickey ER, Studts J, Barringer K, Peng C, Kronkaitis A, Li J, White A, Mische S. Structural basis of constitutive activity and a unique nucleotide binding mode of human Pim-1 kinase. J Biol Chem. 2005;280:6130-6137.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 198]  [Cited by in F6Publishing: 222]  [Article Influence: 11.1]  [Reference Citation Analysis (0)]
19.  Bullock AN, Debreczeni J, Amos AL, Knapp S, Turk BE. Structure and substrate specificity of the Pim-1 kinase. J Biol Chem. 2005;280:41675-41682.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 146]  [Cited by in F6Publishing: 150]  [Article Influence: 7.9]  [Reference Citation Analysis (0)]
20.  Bullock AN, Russo S, Amos A, Pagano N, Bregman H, Debreczeni JE, Lee WH, von Delft F, Meggers E, Knapp S. Crystal structure of the PIM2 kinase in complex with an organoruthenium inhibitor. PLoS One. 2009;4:e7112.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 64]  [Cited by in F6Publishing: 72]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
21.  Kumar A, Mandiyan V, Suzuki Y, Zhang C, Rice J, Tsai J, Artis DR, Ibrahim P, Bremer R. Crystal structures of proto-oncogene kinase Pim1: a target of aberrant somatic hypermutations in diffuse large cell lymphoma. J Mol Biol. 2005;348:183-193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 105]  [Cited by in F6Publishing: 121]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
22.  Jacobs MD, Black J, Futer O, Swenson L, Hare B, Fleming M, Saxena K. Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. J Biol Chem. 2005;280:13728-13734.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 149]  [Article Influence: 7.8]  [Reference Citation Analysis (0)]
23.  Zhang P, Wang H, Min X, Wang Y, Tang J, Cheng J, Li D, Chen X, Cheng F, Wang N. Pim-3 is expressed in endothelial cells and promotes vascular tube formation. J Cell Physiol. 2009;220:82-90.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 25]  [Article Influence: 1.7]  [Reference Citation Analysis (0)]
24.  Lu A, Tang Y, Ran R, Clark JF, Aronow BJ, Sharp FR. Genomics of the periinfarction cortex after focal cerebral ischemia. J Cereb Blood Flow Metab. 2003;23:786-810.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 135]  [Cited by in F6Publishing: 131]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
25.  Liu D, He M, Yi B, Guo WH, Que AL, Zhang JX. Pim-3 protects against cardiomyocyte apoptosis in anoxia/reoxygenation injury via p38-mediated signal pathway. Int J Biochem Cell Biol. 2009;41:2315-2322.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 21]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
26.  Eichmann A, Yuan L, Bréant C, Alitalo K, Koskinen PJ. Developmental expression of pim kinases suggests functions also outside of the hematopoietic system. Oncogene. 2000;19:1215-1224.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 84]  [Cited by in F6Publishing: 87]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
27.  Deneen B, Welford SM, Ho T, Hernandez F, Kurland I, Denny CT. PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins. Mol Cell Biol. 2003;23:3897-3908.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Yang XY, Ren CP, Wang L, Li H, Jiang CJ, Zhang HB, Zhao M, Yao KT. Identification of differentially expressed genes in metastatic and non-metastatic nasopharyngeal carcinoma cells by suppression subtractive hybridization. Cell Oncol. 2005;27:215-223.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Popivanova BK, Li YY, Zheng H, Omura K, Fujii C, Tsuneyama K, Mukaida N. Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis. Cancer Sci. 2007;98:321-328.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 92]  [Cited by in F6Publishing: 100]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
30.  Zheng HC, Tsuneyama K, Takahashi H, Miwa S, Sugiyama T, Popivanova BK, Fujii C, Nomoto K, Mukaida N, Takano Y. Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression. J Cancer Res Clin Oncol. 2008;134:481-488.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 50]  [Cited by in F6Publishing: 61]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
31.  Arvand A, Denny CT. Biology of EWS/ETS fusions in Ewing’s family tumors. Oncogene. 2001;20:5747-5754.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 273]  [Cited by in F6Publishing: 281]  [Article Influence: 12.2]  [Reference Citation Analysis (0)]
32.  Li YY, Wu Y, Tsuneyama K, Baba T, Mukaida N. Essential contribution of Ets-1 to constitutive Pim-3 expression in human pancreatic cancer cells. Cancer Sci. 2009;100:396-404.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 33]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
33.  Aksoy I, Sakabedoyan C, Bourillot PY, Malashicheva AB, Mancip J, Knoblauch K, Afanassieff M, Savatier P. Self-renewal of murine embryonic stem cells is supported by the serine/threonine kinases Pim-1 and Pim-3. Stem Cells. 2007;25:2996-3004.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 58]  [Cited by in F6Publishing: 60]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
34.  Zhu N, Ramirez LM, Lee RL, Magnuson NS, Bishop GA, Gold MR. CD40 signaling in B cells regulates the expression of the Pim-1 kinase via the NF-kappa B pathway. J Immunol. 2002;168:744-754.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Ito H, Duxbury M, Benoit E, Clancy TE, Zinner MJ, Ashley SW, Whang EE. Prostaglandin E2 enhances pancreatic cancer invasiveness through an Ets-1-dependent induction of matrix metalloproteinase-2. Cancer Res. 2004;64:7439-7446.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 106]  [Article Influence: 5.3]  [Reference Citation Analysis (0)]
36.  Safe S, Abdelrahim M. Sp transcription factor family and its role in cancer. Eur J Cancer. 2005;41:2438-2448.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 389]  [Cited by in F6Publishing: 408]  [Article Influence: 21.5]  [Reference Citation Analysis (0)]
37.  Sharrocks AD. The ETS-domain transcription factor family. Nat Rev Mol Cell Biol. 2001;2:827-837.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 762]  [Cited by in F6Publishing: 777]  [Article Influence: 33.8]  [Reference Citation Analysis (0)]
38.  Hoover DS, Wingett DG, Zhang J, Reeves R, Magnuson NS. Pim-1 protein expression is regulated by its 5’-untranslated region and translation initiation factor elF-4E. Cell Growth Differ. 1997;8:1371-1380.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL. eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol. 2006;175:415-426.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 216]  [Cited by in F6Publishing: 209]  [Article Influence: 11.6]  [Reference Citation Analysis (0)]
40.  Ma J, Arnold HK, Lilly MB, Sears RC, Kraft AS. Negative regulation of Pim-1 protein kinase levels by the B56beta subunit of PP2A. Oncogene. 2007;26:5145-5153.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 59]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
41.  Losman JA, Chen XP, Vuong BQ, Fay S, Rothman PB. Protein phosphatase 2A regulates the stability of Pim protein kinases. J Biol Chem. 2003;278:4800-4805.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 49]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
42.  Thomas M, Lange-Grünweller K, Weirauch U, Gutsch D, Aigner A, Grünweller A, Hartmann RK. The proto-oncogene Pim-1 is a target of miR-33a. Oncogene. 2012;31:918-928.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 96]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
43.  Kim KT, Carroll AP, Mashkani B, Cairns MJ, Small D, Scott RJ. MicroRNA-16 is down-regulated in mutated FLT3 expressing murine myeloid FDC-P1 cells and interacts with Pim-1. PLoS One. 2012;7:e44546.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 17]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
44.  Katare R, Caporali A, Zentilin L, Avolio E, Sala-Newby G, Oikawa A, Cesselli D, Beltrami AP, Giacca M, Emanueli C. Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ Res. 2011;108:1238-1251.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 104]  [Article Influence: 8.0]  [Reference Citation Analysis (0)]
45.  Eiring AM, Harb JG, Neviani P, Garton C, Oaks JJ, Spizzo R, Liu S, Schwind S, Santhanam R, Hickey CJ. miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts. Cell. 2010;140:652-665.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 395]  [Cited by in F6Publishing: 382]  [Article Influence: 27.3]  [Reference Citation Analysis (0)]
46.  Huang X, Ding L, Bennewith KL, Tong RT, Welford SM, Ang KK, Story M, Le QT, Giaccia AJ. Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. Mol Cell. 2009;35:856-867.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 447]  [Cited by in F6Publishing: 464]  [Article Influence: 30.9]  [Reference Citation Analysis (0)]
47.  Zhang F, Liu B, Wang Z, Yu XJ, Ni QX, Yang WT, Mukaida N, Li YY. A novel regulatory mechanism of Pim-3 kinase stability and its involvement in pancreatic cancer progression. Mol Cancer Res. 2013;11:1508-1520.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 28]  [Cited by in F6Publishing: 32]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
48.  Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995;80:285-291.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell. 1996;87:619-628.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Aho TL, Sandholm J, Peltola KJ, Mankonen HP, Lilly M, Koskinen PJ. Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett. 2004;571:43-49.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 254]  [Cited by in F6Publishing: 271]  [Article Influence: 13.6]  [Reference Citation Analysis (0)]
51.  Yan B, Zemskova M, Holder S, Chin V, Kraft A, Koskinen PJ, Lilly M. The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem. 2003;278:45358-45367.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 201]  [Cited by in F6Publishing: 211]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
52.  Liu LM, Zhang JX, Wang XP, Guo HX, Deng H, Luo J. Pim-3 protects against hepatic failure in D-galactosamine (D-GalN)-sensitized rats. Eur J Clin Invest. 2010;40:127-138.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 17]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
53.  Breggia AC, Wojchowski DM, Himmelfarb J. JAK2/Y343/STAT5 signaling axis is required for erythropoietin-mediated protection against ischemic injury in primary renal tubular epithelial cells. Am J Physiol Renal Physiol. 2008;295:F1689-F1695.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 17]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
54.  Chang M, Kanwar N, Feng E, Siu A, Liu X, Ma D, Jongstra J. PIM kinase inhibitors downregulate STAT3(Tyr705) phosphorylation. Mol Cancer Ther. 2010;9:2478-2487.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 39]  [Cited by in F6Publishing: 41]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
55.  Zhang Y, Wang Z, Li X, Magnuson NS. Pim kinase-dependent inhibition of c-Myc degradation. Oncogene. 2008;27:4809-4819.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 166]  [Cited by in F6Publishing: 180]  [Article Influence: 11.3]  [Reference Citation Analysis (0)]
56.  Winn LM, Lei W, Ness SA. Pim-1 phosphorylates the DNA binding domain of c-Myb. Cell Cycle. 2003;2:258-262.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Chen XP, Losman JA, Cowan S, Donahue E, Fay S, Vuong BQ, Nawijn MC, Capece D, Cohan VL, Rothman P. Pim serine/threonine kinases regulate the stability of Socs-1 protein. Proc Natl Acad Sci USA. 2002;99:2175-2180.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 145]  [Cited by in F6Publishing: 154]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
58.  Peltola KJ, Paukku K, Aho TL, Ruuska M, Silvennoinen O, Koskinen PJ. Pim-1 kinase inhibits STAT5-dependent transcription via its interactions with SOCS1 and SOCS3. Blood. 2004;103:3744-3750.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 95]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
59.  Gu JJ, Wang Z, Reeves R, Magnuson NS. PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene. 2009;28:4261-4271.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 83]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
60.  Peng C, Knebel A, Morrice NA, Li X, Barringer K, Li J, Jakes S, Werneburg B, Wang L. Pim kinase substrate identification and specificity. J Biochem. 2007;141:353-362.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 49]  [Cited by in F6Publishing: 59]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
61.  Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y. Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway. J Biol Chem. 1999;274:18659-18666.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Bachmann M, Hennemann H, Xing PX, Hoffmann I, Möröy T. The oncogenic serine/threonine kinase Pim-1 phosphorylates and inhibits the activity of Cdc25C-associated kinase 1 (C-TAK1): a novel role for Pim-1 at the G2/M cell cycle checkpoint. J Biol Chem. 2004;279:48319-48328.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 104]  [Cited by in F6Publishing: 110]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
63.  Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS. Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta. 2002;1593:45-55.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Zhang Y, Wang Z, Magnuson NS. Pim-1 kinase-dependent phosphorylation of p21Cip1/WAF1 regulates its stability and cellular localization in H1299 cells. Mol Cancer Res. 2007;5:909-922.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 97]  [Article Influence: 5.7]  [Reference Citation Analysis (0)]
65.  Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008;68:5076-5085.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 214]  [Cited by in F6Publishing: 225]  [Article Influence: 14.1]  [Reference Citation Analysis (0)]
66.  Wang YY, Taniguchi T, Baba T, Li YY, Ishibashi H, Mukaida N. Identification of a phenanthrene derivative as a potent anticancer drug with Pim kinase inhibitory activity. Cancer Sci. 2012;103:107-115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 14]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
67.  Wu Y, Wang YY, Nakamoto Y, Li YY, Baba T, Kaneko S, Fujii C, Mukaida N. Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver. Oncogene. 2010;29:2228-2237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 49]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
68.  Mikkers H, Nawijn M, Allen J, Brouwers C, Verhoeven E, Jonkers J, Berns A. Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol. 2004;24:6104-6115.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 241]  [Cited by in F6Publishing: 255]  [Article Influence: 12.8]  [Reference Citation Analysis (0)]
69.  Beharry Z, Mahajan S, Zemskova M, Lin YW, Tholanikunnel BG, Xia Z, Smith CD, Kraft AS. The Pim protein kinases regulate energy metabolism and cell growth. Proc Natl Acad Sci USA. 2011;108:528-533.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 97]  [Article Influence: 6.9]  [Reference Citation Analysis (0)]
70.  Zippo A, De Robertis A, Serafini R, Oliviero S. PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation. Nat Cell Biol. 2007;9:932-944.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 195]  [Cited by in F6Publishing: 209]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
71.  Vlacich G, Nawijn MC, Webb GC, Steiner DF. Pim3 negatively regulates glucose-stimulated insulin secretion. Islets. 2010;2:308-317.  [PubMed]  [DOI]  [Cited in This Article: ]
72.  Amaravadi R, Thompson CB. The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest. 2005;115:2618-2624.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 315]  [Cited by in F6Publishing: 324]  [Article Influence: 17.1]  [Reference Citation Analysis (0)]
73.  Lindsley CW. The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update. Curr Top Med Chem. 2010;10:458-477.  [PubMed]  [DOI]  [Cited in This Article: ]
74.  Cheng F, Weidner-Glunde M, Varjosalo M, Rainio EM, Lehtonen A, Schulz TF, Koskinen PJ, Taipale J, Ojala PM. KSHV reactivation from latency requires Pim-1 and Pim-3 kinases to inactivate the latency-associated nuclear antigen LANA. PLoS Pathog. 2009;5:e1000324.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 55]  [Article Influence: 3.7]  [Reference Citation Analysis (0)]
75.  Major MB, Roberts BS, Berndt JD, Marine S, Anastas J, Chung N, Ferrer M, Yi X, Stoick-Cooper CL, von Haller PD. New regulators of Wnt/beta-catenin signaling revealed by integrative molecular screening. Sci Signal. 2008;1:ra12.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 100]  [Cited by in F6Publishing: 120]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
76.  Verbeek S, van Lohuizen M, van der Valk M, Domen J, Kraal G, Berns A. Mice bearing the E mu-myc and E mu-pim-1 transgenes develop pre-B-cell leukemia prenatally. Mol Cell Biol. 1991;11:1176-1179.  [PubMed]  [DOI]  [Cited in This Article: ]
77.  Yang H, Wang Y, Qian H, Zhang P, Huang C. Pim protein kinase-3 is regulated by TNF-α and promotes endothelial cell sprouting. Mol Cells. 2011;32:235-241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 14]  [Cited by in F6Publishing: 12]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
78.  Red-Horse K, Crawford Y, Shojaei F, Ferrara N. Endothelium-microenvironment interactions in the developing embryo and in the adult. Dev Cell. 2007;12:181-194.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 96]  [Cited by in F6Publishing: 103]  [Article Influence: 6.1]  [Reference Citation Analysis (0)]
79.  Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967-974.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1925]  [Cited by in F6Publishing: 1925]  [Article Influence: 106.9]  [Reference Citation Analysis (0)]
80.  Niedergethmann M, Hildenbrand R, Wostbrock B, Hartel M, Sturm JW, Richter A, Post S. High expression of vascular endothelial growth factor predicts early recurrence and poor prognosis after curative resection for ductal adenocarcinoma of the pancreas. Pancreas. 2002;25:122-129.  [PubMed]  [DOI]  [Cited in This Article: ]
81.  Wang C, Li HY, Liu B, Huang S, Wu L, Li YY. Pim-3 promotes the growth of human pancreatic cancer in the orthotopic nude mouse model through vascular endothelium growth factor. J Surg Res. 2013;185:595-604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 10]  [Article Influence: 0.9]  [Reference Citation Analysis (0)]
82.  Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF. Heterogeneity of the tumor vasculature. Semin Thromb Hemost. 2010;36:321-331.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 240]  [Cited by in F6Publishing: 249]  [Article Influence: 17.8]  [Reference Citation Analysis (0)]
83.  Shah N, Pang B, Yeoh KG, Thorn S, Chen CS, Lilly MB, Salto-Tellez M. Potential roles for the PIM1 kinase in human cancer - a molecular and therapeutic appraisal. Eur J Cancer. 2008;44:2144-2151.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 112]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
84.  Bachmann M, Möröy T. The serine/threonine kinase Pim-1. Int J Biochem Cell Biol. 2005;37:726-730.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 266]  [Cited by in F6Publishing: 272]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
85.  Weirauch U, Beckmann N, Thomas M, Grünweller A, Huber K, Bracher F, Hartmann RK, Aigner A. Functional role and therapeutic potential of the pim-1 kinase in colon carcinoma. Neoplasia. 2013;15:783-794.  [PubMed]  [DOI]  [Cited in This Article: ]
86.  Guo S, Mao X, Chen J, Huang B, Jin C, Xu Z, Qiu S. Overexpression of Pim-1 in bladder cancer. J Exp Clin Cancer Res. 2010;29:161.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 62]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
87.  Nga ME, Swe NN, Chen KT, Shen L, Lilly MB, Chan SP, Salto-Tellez M, Das K. PIM-1 kinase expression in adipocytic neoplasms: diagnostic and biological implications. Int J Exp Pathol. 2010;91:34-43.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 19]  [Article Influence: 1.3]  [Reference Citation Analysis (0)]
88.  Hu XF, Li J, Vandervalk S, Wang Z, Magnuson NS, Xing PX. PIM-1-specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis. J Clin Invest. 2009;119:362-375.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 46]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
89.  Morishita D, Takami M, Yoshikawa S, Katayama R, Sato S, Kukimoto-Niino M, Umehara T, Shirouzu M, Sekimizu K, Yokoyama S. Cell-permeable carboxyl-terminal p27(Kip1) peptide exhibits anti-tumor activity by inhibiting Pim-1 kinase. J Biol Chem. 2011;286:2681-2688.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 28]  [Article Influence: 2.0]  [Reference Citation Analysis (0)]
90.  Holder S, Zemskova M, Zhang C, Tabrizizad M, Bremer R, Neidigh JW, Lilly MB. Characterization of a potent and selective small-molecule inhibitor of the PIM1 kinase. Mol Cancer Ther. 2007;6:163-172.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 132]  [Cited by in F6Publishing: 138]  [Article Influence: 8.1]  [Reference Citation Analysis (0)]
91.  Chen LS, Redkar S, Bearss D, Wierda WG, Gandhi V. Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. Blood. 2009;114:4150-4157.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 155]  [Cited by in F6Publishing: 161]  [Article Influence: 10.7]  [Reference Citation Analysis (0)]
92.  Pogacic V, Bullock AN, Fedorov O, Filippakopoulos P, Gasser C, Biondi A, Meyer-Monard S, Knapp S, Schwaller J. Structural analysis identifies imidazo[1,2-b]pyridazines as PIM kinase inhibitors with in vitro antileukemic activity. Cancer Res. 2007;67:6916-6924.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 157]  [Cited by in F6Publishing: 162]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
93.  Dakin LA, Block MH, Chen H, Code E, Dowling JE, Feng X, Ferguson AD, Green I, Hird AW, Howard T. Discovery of novel benzylidene-1,3-thiazolidine-2,4-diones as potent and selective inhibitors of the PIM-1, PIM-2, and PIM-3 protein kinases. Bioorg Med Chem Lett. 2012;22:4599-4604.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 87]  [Article Influence: 7.3]  [Reference Citation Analysis (0)]
94.  Xia Z, Knaak C, Ma J, Beharry ZM, McInnes C, Wang W, Kraft AS, Smith CD. Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases. J Med Chem. 2009;52:74-86.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 142]  [Cited by in F6Publishing: 149]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
95.  Lin YW, Beharry ZM, Hill EG, Song JH, Wang W, Xia Z, Zhang Z, Aplan PD, Aster JC, Smith CD. A small molecule inhibitor of Pim protein kinases blocks the growth of precursor T-cell lymphoblastic leukemia/lymphoma. Blood. 2010;115:824-833.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 98]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
96.  Nishiguchi GA, Atallah G, Bellamacina C, Burger MT, Ding Y, Feucht PH, Garcia PD, Han W, Klivansky L, Lindvall M. Discovery of novel 3,5-disubstituted indole derivatives as potent inhibitors of Pim-1, Pim-2, and Pim-3 protein kinases. Bioorg Med Chem Lett. 2011;21:6366-6369.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 47]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
97.  Gavara L, Saugues E, Alves G, Debiton E, Anizon F, Moreau P. Synthesis and biological activities of pyrazolo[3,4-g]quinoxaline derivatives. Eur J Med Chem. 2010;45:5520-5526.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 23]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
98.  Suchaud V, Gavara L, Saugues E, Nauton L, Théry V, Anizon F, Moreau P. Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors. Bioorg Med Chem. 2013;21:4102-4111.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
99.  Akué-Gédu R, Letribot B, Saugues E, Debiton E, Anizon F, Moreau P. Kinase inhibitory potencies and in vitro antiproliferative activities of N-10 substituted pyrrolo[2,3-a]carbazole derivatives. Bioorg Med Chem Lett. 2012;22:3807-3809.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 26]  [Cited by in F6Publishing: 23]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
100.  Gavara L, Suchaud V, Nauton L, Théry V, Anizon F, Moreau P. Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors. Bioorg Med Chem Lett. 2013;23:2298-2301.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 21]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
101.  Letribot B, Akué-Gédu R, Santio NM, El-Ghozzi M, Avignant D, Cisnetti F, Koskinen PJ, Gautier A, Anizon F, Moreau P. Use of copper(I) catalyzed azide alkyne cycloaddition (CuAAC) for the preparation of conjugated pyrrolo[2,3-a]carbazole Pim kinase inhibitors. Eur J Med Chem. 2012;50:304-310.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 21]  [Cited by in F6Publishing: 23]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
102.  Li YY, Wang YY, Taniguchi T, Kawakami T, Baba T, Ishibashi H, Mukaida N. Identification of stemonamide synthetic intermediates as a novel potent anticancer drug with an apoptosis-inducing ability. Int J Cancer. 2010;127:474-484.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1]  [Cited by in F6Publishing: 5]  [Article Influence: 0.4]  [Reference Citation Analysis (0)]
103.  Wang Z, Li XM, Shang K, Zhang P, Wang CF, Xin YH, Zhou L, Li YY. T-18, a stemonamide synthetic intermediate inhibits Pim kinase activity and induces cell apoptosis, acting as a potent anticancer drug. Oncol Rep. 2013;29:1245-1251.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7]  [Cited by in F6Publishing: 8]  [Article Influence: 0.7]  [Reference Citation Analysis (0)]
104.  Akué-Gédu R, Rossignol E, Azzaro S, Knapp S, Filippakopoulos P, Bullock AN, Bain J, Cohen P, Prudhomme M, Anizon F. Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors. J Med Chem. 2009;52:6369-6381.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 73]  [Cited by in F6Publishing: 77]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
105.  Rhodes N, Heerding DA, Duckett DR, Eberwein DJ, Knick VB, Lansing TJ, McConnell RT, Gilmer TM, Zhang SY, Robell K. Characterization of an Akt kinase inhibitor with potent pharmacodynamic and antitumor activity. Cancer Res. 2008;68:2366-2374.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 214]  [Cited by in F6Publishing: 222]  [Article Influence: 13.9]  [Reference Citation Analysis (0)]
106.  Chen WS, Xu PZ, Gottlob K, Chen ML, Sokol K, Shiyanova T, Roninson I, Weng W, Suzuki R, Tobe K. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 2001;15:2203-2208.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 679]  [Cited by in F6Publishing: 708]  [Article Influence: 30.8]  [Reference Citation Analysis (0)]
107.  Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS, Lee VM, Szabolcs M, de Jong R, Oltersdorf T. Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol. 2005;25:1869-1878.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 419]  [Cited by in F6Publishing: 456]  [Article Influence: 24.0]  [Reference Citation Analysis (0)]
108.  Woulfe D, Jiang H, Morgans A, Monks R, Birnbaum M, Brass LF. Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J Clin Invest. 2004;113:441-450.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 87]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]