Polo-like kinase 3 and phosphoT273 caspase-8 are associated with improved local tumor control and survival in patients with anal carcinoma treated with concomitant chemoradiotherapy.

Franz Rödel,Christina Helmke,Daniel Martin,Ulrike Wieland,Julia Kitz,Panagiotis Balermpas,Margret Rave-Fränk,Klaus Strebhardt,Claus Rödel,Emmanouil Fokas,Yves Matthess,Monika Raab

doi:10.18632/oncotarget.10801

Franz Rödel, Christina Helmke + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.10801

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Abstract

We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function. In the present study we aimed to investigate the clinical relevance of Plk3 expression and phosphorylation of caspase-8 at T273 in patients with anal squamous cell carcinoma (SSC) treated with 5-fluorouracil and mitomycin C-based chemoradiotherapy (CRT). Immunohistochemical detection of the markers was performed in pretreatment biopsy specimens of 95 patients and was correlated with clinical/histopathologic characteristics including HPV-16 virus load/p16INK4a expression and cumulative incidence of local and distant failure, cancer specific survival (CSS), and overall survival (OS). We observed significant positive correlations between Plk3 expression, pT273 caspase-8 signal, and levels of HPV-16 virus DNA load/p16INK4a detection. Patients with high scores of Plk3 and pT273 caspase-8 showed increased local control (p = 0.011; p = 0.001), increased CSS (p = 0.011; p = 0.013) and OS (p = 0.024; p = 0.001), while the levels of pT273 caspase-8 were significantly associated (p = 0.033) with distant metastases. In multivariate analyses Plk3 expression remained significant for local failure (p = 0.018), CSS (p = 0.016) and OS (p = 0.023). Moreover, a combined HPV16 DNA load and Plk3 or pT273 caspase-8 variable revealed a significant correlation to decreased local failure (p = 0.001; p = 0.009), increased CSS (p = 0.016; p = 0.023) and OS (p = 0.003; p = 0.003). In conclusion these data indicate that elevated levels of Plk3 and pT273 caspase-8 are correlated with favorable clinical outcome in patients with anal SCC treated with concomitant CRT.

Highlights

Polo-like-kinases (Plks) are master regulators of cell cycle progression, entry into mitosis, DNA replication and checkpoint regulation [1,2,3]
We have recently shown that caspase-8 is a new substrate of Polo-like kinase 3 (Plk3) that phosphorylates the protein on residue T273 thereby promoting its pro-apoptotic function
Plk3 kinase activity is rapidly increased upon oxidative stress or DNA damage in an Ataxia telangiectasia mutated (ATM) kinase-dependent manner resulting in phosphorylation of the tumor suppressor TP53 and checkpoint kinase 2 (Chk2), linking DNA damage to cell cycle arrest and apoptosis [3, 14]

Summary

Introduction

Polo-like-kinases (Plks) are master regulators of cell cycle progression, entry into mitosis, DNA replication and checkpoint regulation [1,2,3]. Various ATP-competitive small molecule Plk inhibitors successfully entered the clinics including BI 6727 (Volasertib®) and demonstrated survival benefit in patients with acute myeloid leukemia [8]. These drugs, inhibit the activity of the Plk1-related family members Plk and Plk3 [9] indicating the necessity for a careful consideration of the role of these proteins in oncogenesis and treatment response. We have recently identified Plk as a novel interaction partner of the death receptor CD95 and caspase-8 as a new substrate of Plk that phosphorylates pro-caspase-8 on residue T273, thereby promoting its pro-apoptotic function upon CD95 or related apoptosis-inducing ligand (TRAIL) stimulation [15]. Plk has a tumor suppressor role in hepatocellular (HCC) and head and neck squamous cell carcinoma (HNSCC) [17,18,19], while overexpression was correlated with shortened relapse-free survival time in breast and ovarian cancer [20, 21]

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