Pim-1 Kinase Expression Predicts Radiation Response in Squamocellular Carcinoma of Head and Neck and Is under the Control of Epidermal Growth Factor Receptor

Abstract

Pim-1 is an oncogenic serine/threonine kinase with poorly defined function in epithelial cancers. In this study, we determined 1) associations of Pim-1 expression with clinicopathological parameters including responsiveness to irradiation in squamocellular cancers of head and neck and 2) how Pim-1 expression is controlled subsequent to irradiation. Moderate to high expression of Pim-1 correlated to poor response to radiation therapy (P = .003). It is also associated to the expression of epidermal growth factor receptor (EGFR, P < .0001), which has been shown to be activated by irradiation. In radioresistant tumors, irradiation promoted nuclear translocation of Pim-1 (P < .005). When directly testing EGFR dependence of Pim-1 expression, up-regulation and nuclear translocation of Pim-1 could be induced through stimulation of EGFR with its ligands EGF or transforming growth factor alpha. Both ligand- and irradiation-induced changes in Pim-1 expression and localization could be inhibited by the monoclonal anti-EGFR antibody cetuximab and by the tyrosine kinase inhibitor gefitinib also targeting EGFR. These results suggest that irradiation-induced activation of EGFR upregulates Pim-1, and Pim-1 may be used as a novel predictive marker of radiation response in patients with squamocellular cancers of head and neck.

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells

“…Consistent with our previous data, it has been reported that PIM1 is overexpressed in malignant keratinocytes in head and neck squamous cell carcinoma (HNSCC) and moderate/high PIM1 expression levels tend to be associated with poor prognosis in HNSCC compared to low/negative PIM1 expression [25]. In addition, the expression of PIM1 is also significantly associated with the expression of EGFR, which has been previously demonstrated to promote radioresistance [25,26]. Because the classic prognostic markers such as tumor size, nodal status, or histological grade cannot be used to predict responses to radiotherapy, and there are currently no generally accepted clinical markers for predicting radiosensitivity, these results may have clinical implication.…”

“…Under these conditions, PIM1-activated pPRAS40, AKT-activated pFOXO3a, and complexes formed by these two proteins and 14-3-3 could be key regulators of IR-induced radioresistance in NSCLC cells. Consistent with our previous data, it has been reported that PIM1 is overexpressed in malignant keratinocytes in head and neck squamous cell carcinoma (HNSCC) and moderate/high PIM1 expression levels tend to be associated with poor prognosis in HNSCC compared to low/negative PIM1 expression [25]. In addition, the expression of PIM1 is also significantly associated with the expression of EGFR, which has been previously demonstrated to promote radioresistance [25,26].…”

Proto-oncogene PIM-1 is a novel estrogen receptor target associating with high grade breast tumors

“…However, investigation of a larger sample set of breast cancers is warranted to further corroborate this. Previously, increased expression of PIM-1 among non-hematological malignancies has been associated with poor prognosis of patients with esophageal squamous cell carcinoma and shown to predict poor radiation response in squamocellular carcinoma of head and neck (Xie et al, 2006;Mumenthaler et al, 2009;Peltola et al, 2009;Liu et al, 2010). In sum, our data indicate that the proto-oncogene PIM-1 is a potential estrogen target in breast cancer cells and that the elevated PIM-1 expression is associated with the increased invasiveness of breast cancer tumors.…”

Aberrant Expression of Pim-3 Promotes Proliferation and Migration of Ovarian Cancer Cells

“…Since Pim kinase expression has been associated with poor outcome in several different tumor types (Wright et al, 2003;Dave et al, 2006;Rossi et al, 2006;Zheng et al, 2008;Peltola et al, 2009;Warnecke-Eberz et al, 2009) al., 2009), inhibition of Pim kinases has evoked a lot of interest and inspired efforts has been conducted to inhibit the Pim kinases as a potential tragedy of cancer treatment. Moreover, the triple knockout Pim kinase mice are viable and fertile, which suggests that inhibition of the Pim kinase family could be possible without severe side effects (Mikkers et al, 2004).…”