RESUMEN
INTRODUCTION: Glucose metabolism in cancer cells differs from noncancerous cells. The expression of transketolase-like protein 1 (TKTL1), a key enzyme in the glucose metabolism of cancer cells, predicts poor prognosis in several cancer types. We studied TKTL1 as a prognostic tool and whether TKTL1 expression correlates with 18F-FDG-PET-CT among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective study examined two PDAC patient cohorts: 168 patients operated on at Helsinki University Hospital between 2001 and 2011, and 20 patients with FDG-PET-CT results available from the Auria Biobank. We used immunohistochemistry for TKTL1 expression, combining results with clinicopathological data. RESULTS: Five-year disease-specific survival (DSS) was slightly but not significantly better in patients with a high versus low TKTL1 expression, with DSS of 28.0 versus 17.3%, respectively (p = 0.123). TKTL1 served as a marker of a better prognosis in patients over 65 years old (p = 0.012) and among those with TNM class M1 (p = 0.018), stage IV disease (p = 0.027), or perivascular invasion (p = 0.008). CONCLUSIONS: Our study shows that TKTL1 cannot be used as a prognostic factor in PDAC with the exception of elderly patients and those with advanced disease. The correlation of TKTL1 with 18F-FDG-PET-CT requires further study in a larger patient cohort.
Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/metabolismo , Fluorodesoxiglucosa F18 , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/metabolismo , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Transcetolasa/análisis , Transcetolasa/metabolismo , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Pronóstico , Estudios RetrospectivosRESUMEN
Transketolase is a connecting link between glycolytic and pentose phosphate pathway, which is considered as the rate-limiting step due to synthesis of large number of ATP molecule and it can be proposed as a plausible target facilitating the growth of cancerous cells suggesting its potential role in cancer. Oxythiamine, an antimetabolite has been proved to be an efficient anticancerous compound in vitro, but its structural elucidation of the inhibitory mechanism has not yet been done against the human transketolase-like 1 protein (TKTL1). The three-dimensional (3D) structure of TKTL1 protein was modeled and subjected for refinement, stability and validation. Based on the reported homologs of transketolase (TKT), the active site residues His46, Ser49, Ser52, Ser53, Ile56, Leu82, Lys84, Leu123, Ser125, Glu128, Asp154, His160, Thr216 and Lys218 were identified and considered for molecular-modeling studies. Docking studies reveal the H-bond interactions with residues Ser49 and Lys218 that could play a major role in the activity of TKTL1. Molecular dynamics (MD) simulation study was performed to reveal the comparative stability of both native and complex forms of TKTL1. MD trajectory at 30 ns, confirm the role of active site residues Ser49, Lys84, Glu128, His160 and Lys218 in suppressing the activity of TKTL1. Glu128 is observed to be the most important residue for deprotonation state of the aminopyrimidine moiety and preferred to be the site of inhibitory action. Thus, the proposed mechanism of inhibition through in silico studies would pave the way for structure-oriented drug designing against cancer.