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

English version

Autoři: Parmanand Malvi ^aff001; Radoslav Janostiak ^aff002; Arvindhan Nagarajan ^aff002; Guoping Cai ^aff002; Narendra Wajapeyee ^aff001
Působiště autorů: Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America ^aff001; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America ^aff002
Vyšlo v časopise: Loss of thymidine kinase 1 inhibits lung cancer growth and metastatic attributes by reducing GDF15 expression. PLoS Genet 15(10): e1008439. doi:10.1371/journal.pgen.1008439
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008439

Souhrn

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.

Klíčová slova:

Adenocarcinoma of the lung – Gene expression – Immunoblot analysis – Lung and intrathoracic tumors – Metastasis – Metastatic tumors – Secondary lung tumors – Squamous cell lung carcinoma

Zdroje

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