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

Abstract

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...

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

“…59 PIM1 expression is maintained during androgen deprivation therapy in mice, implying that it may be important for maintenance of proliferation in this setting. 111 AR levels do not appear to affect PIM1, which would suggest a promising approach for co-targeting, as the two are independently expressed. Investigations combining PIM inhibition and ADT are needed to assess whether the inhibition of PIM could overcome resistance to ADT.…”

Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

“…Androgen deprivation therapy (ADT) did not affect PIM1 expression and it is hypothesized that PIM1 may be important in the proliferation and differentiation of prostate cancer during ADT (Wang et al, 2017) had no effect on the growth of primary prostate cells alone, when AZD1208 was added to co-cultures of BPH1 cells and PIM1 overexpressing fibroblasts, the ability of the fibroblasts to enhance BPH1 proliferation was reduced. These data suggest that the fibroblast to CAF transition and the ability of CAFs to stimulate prostate epithelial cell growth is enhanced by PIM1 activity.…”

Reduced pim‑1 expression increases chemotherapeutic drug sensitivity in human androgen‑independent prostate cancer cells by inducing apoptosis

“…In particular, pim-1 serves an important role in the induction or suppression of cell cycle progression and apoptosis. In a previous study, immunohistochemical analysis was used to characterize the expression patterns of pim-1 in high grade prostatic cancer tissues and normal tissues (10). The expression of pim-1 in prostate cancer tissues was demonstrated to be significantly higher compared with that in normal prostate tissues and benign prostatic hyperplasia (9).…”