Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression.

Parmanand Malvi,Narendra Wajapeyee,Arvindhan Nagarajan,Radoslav Janostiak,Guoping Cai,Kent W Hunter

doi:10.1371/journal.pgen.1008439

Parmanand Malvi, Narendra Wajapeyee + Show 4 more

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https://doi.org/10.1371/journal.pgen.1008439

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Abstract

Metabolic alterations that are critical for cancer cell growth and metastasis are one of the key hallmarks of cancer. Here, we show that thymidine kinase 1 (TK1) is significantly overexpressed in tumor samples from lung adenocarcinoma (LUAD) patients relative to normal controls, and this TK1 overexpression is associated with significantly reduced overall survival and cancer recurrence. Genetic knockdown of TK1 with short hairpin RNAs (shRNAs) inhibits both the growth and metastatic attributes of LUAD cells in culture and in mice. We further show that transcriptional overexpression of TK1 in LUAD cells is driven, in part, by MAP kinase pathway in a transcription factor MAZ dependent manner. Using targeted and gene expression profiling-based approaches, we then show that loss of TK1 in LUAD cells results in reduced Rho GTPase activity and reduced expression of growth and differentiation factor 15 (GDF15). Furthermore, ectopic expression of GDF15 can partially rescue TK1 knockdown-induced LUAD growth and metastasis inhibition, confirming its important role as a downstream mediator of TK1 function in LUAD. Collectively, our findings demonstrate that TK1 facilitates LUAD tumor and metastatic growth and represents a target for LUAD therapy.

Highlights

Lung cancer is the leading cause of cancer-related deaths in both men and women
Thymidine kinase 1 (TK1) is overexpressed and associated with poor prognosis in a number of different cancers. Despite these data suggesting an important role for TK1 in cancer pathogenesis, no study far has analyzed the functional effect of TK1 inhibition on tumor growth and metastasis
We performed TK1 knockdown and found that this protein is necessary for lung adenocarcinoma (LUAD) tumor growth and metastasis

Summary

Introduction

Non-small cell lung cancer (NSCLC) accounts for ~80% of lung cancers, with lung adenocarcinoma (LUAD) constituting the most common type of NSCLC [1,2,3]. The severity of this disease and the limitations of current therapies, including immunotherapies, are highlighted by the fact that the five-year survival rate for LUAD patients with stage IIIB and stage IV disease is only 5% and 1%, respectively [1,2,3]. The specific metabolic needs of cancer cells have emerged as important cancer cell hallmarks [5,6,7,8]. Other metabolic enzymes, such as pyruvate carboxylase (PC), and metabolic pathways, such as the glutamine pathway and the de novo lipogenesis pathway, have been shown to be important for NSCLC cell survival [13,14,15]

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