Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Hsu, Jung Mao; Leong, Pui-Kei; Ho, Yunn‐Fang; Hsu, Lih‐Ching; Lu, Pin-Hsuan; Chen, Ching‐Shih; Guh, Jih‐Hwa

doi:10.1016/j.canlet.2012.01.004

Cited by 22 publications

(18 citation statements)

References 37 publications

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“…Similarly, inhibition of Pim kinase in T-cell lymphoma cells downregulated genes involved in DNA repair, including XRCC2 (HR) , XRCC5 (encoding Ku80, in the NHEJ pathway), and ERCC8 (nucleotide excision repair) [36]. Pim kinase inhibition was also found to potentiate paclitaxel-induced apoptosis through decreased repair via the NHEJ pathway, with inhibition of ATM, DNA-PKcs and Ku activity and/or expression [58]. Notably, cells with FLT3-ITD exhibit downregulation of classical NHEJ, and upregulation of the alt-NHEJ pathway, which is error-prone [50, 51].…”

Section: Discussionmentioning

confidence: 99%

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

et al. 2016

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Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD.

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Section: Discussionmentioning

confidence: 99%

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

et al. 2016

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“…PIM‐1 seems to play an essential role in the regulation of nonhomologous end joining repair, as the inhibition of PIM1 enhanced the apoptotic cell death caused by agents, such as paclitaxel that blocked the ATM‐dependent DNA repair system …”

Section: Pim Kinases As a Therapeutic Targetmentioning

confidence: 99%

The PIM Family of Serine/Threonine Kinases in Cancer

Narlik-Grassow

Blanco‐Aparicio

Carnero

2013

Medicinal Research Reviews

195

192

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The proviral insertion site in Moloney murine leukemia virus, or PIM proteins, are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM2, and PIM3) that are highly evolutionarily conserved. These proteins are regulated primarily by transcription and stability through pathways that are controlled by Janus kinase/Signal transducer and activator of transcription, JAK/STAT, transcription factors. The PIM family proteins have been found to be overexpressed in hematological malignancies and solid tumors, and their roles in these tumors were confirmed in mouse tumor models. Furthermore, the PIM family proteins have been implicated in the regulation of apoptosis, metabolism, cell cycle, and homing and migration, which has led to the postulation of these proteins as interesting targets for anticancer drug discovery. In the present work, we review the importance of PIM kinases in tumor growth and as drug targets.

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“…In a previous study, the decreased AR expression coincided with increased Pim-1 expression, indicating that Pim-1 may contribute to regulation of AR turnover (21). AR is critical in prostate cancer development to CRPC, therefore, Pim-1 may serve as a potential target for the treatment of hormone-refractory prostate cancer (22). However, the molecular mechanisms of Pim kinases in specific signaling pathways for prostate cancer cell proliferation and progression are complicated and not well established (11).…”

Section: Discussionmentioning

confidence: 86%

“…Cytotoxic drugs such as docetaxel activate Pim-1 kinase in DU145 cells (27). The ability of DNA repair significantly decreases in the absence of Pim-1, leading to severe DNA damage and apoptosis (22).…”

Section: Discussionmentioning

confidence: 99%

Androgen deprivation therapy has no effect on Pim-1 expression in a mouse model of prostate cancer

Wang

Лі

et al. 2017

Oncology Letters

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Abstract. The aim of the present study was to observe the dynamic changes of proto-oncogene, serine/threonine kinase, Pim-1 at the gene and protein level in a mouse model of prostate cancer following surgical castration. Using LNCaP cells to establish a subcutaneous xenograft model and orthotopic prostate cancer BALB/c nude mouse models, the xenograft models were divided into an androgen-dependent prostate cancer group (ADPC), an androgen deprivation therapy (ADT) group and an androgen independent prostate cancer (AIPC) group. Reverse transcription-polymerase chain reaction (RT-PCR), RT-quantitative PCR, ELISA and immunohistochemistry analyses were performed to compare the expression levels of Pim-1, prostate-specific antigen (PSA) and androgen receptor (AR) in tumor tissue of three subgroups. Agarose gel electrophoresis revealed that the RT-PCR results of the ADPC (0.59±0.01) and AIPC groups (1.14±0.015) were significantly different when compared with the ADT group (0.62±0.026; P<0.05). As for RT-qPCR, the ΔCq of Pim-1 in the ADPC (6.15±0.34) and AIPC (4.56±0.23) groups were significantly different compared with the ADT group (5.11±0.21; P<0.05). Using 2 -ΔΔCq as a relative quantification method to analyze the data, the amplification products of Pim-1 increased by 2.05 and 3.01 times in the ADT and AIPC groups, respectively. ELISA demonstrated the following: The serum concentration of PSA was 0 ng/ml in the control group, 0.48±0.025 ng/ml in the ADPC group and 0.87±0.023 ng/ml in the AIPC group, which were significantly different compared with the ADT group (0.17±0.032 ng/ml; P<0.01). Upon immunohistochemical staining, the protein expression levels of Pim-1 and AR, respectively, were 0.017±0.0021 and 0.032±0.009 in the ADPC group, 0.024±0.0019 and 0.040±0.011 in the AIPC group, and 0.018±0.0013 and 0.019±0.006 in the ADT group. The protein levels of Pim-1 and AR in the ADPC and AIPC groups were significantly different compared with the ADT group (P<0.01). In addition, an orthotopic prostate cancer animal model of ADT was successfully established in the current study, and further investigation revealed that ADT did not affect the expression of Pim-1 at the gene or protein levels; thus, it is hypothesized that Pim-1 may be important in the proliferation and differentiation of prostate cancer during ADT. IntroductionHuman proviral integration site for Moloney murine leukemia virus (Pim) is a proto-oncogene that was initially recognized 20 years ago (1); further studies have revealed that Pim encodes serine/threonine kinase and functions as a signaling regulator through cellular substrate phosphorylation (2,3). Pim participates in multiple biological functions, including numerous cellular signaling pathways, and regulates cell cycle progression, cell proliferation and differentiation, and inhibits apoptosis. Recently, the association between androgen receptor (AR) and the proto-oncogene, serine/threonine kinase, Pim-1, has been shown to be strong, and studies have indicated that Pim-1 is expressed in androgen-depen...

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Pim-1 knockdown potentiates paclitaxel-induced apoptosis in human hormone-refractory prostate cancers through inhibition of NHEJ DNA repair

Cited by 22 publications

References 37 publications

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

The PIM Family of Serine/Threonine Kinases in Cancer

Androgen deprivation therapy has no effect on Pim-1 expression in a mouse model of prostate cancer

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