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

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. Author summary Thymidine kinase 1 (TK1) is overexpressed and associated with poor prognosis in a number of different cancers. However, despite these data suggesting an important role for TK1 in cancer pathogenesis, no study thus far has analyzed the functional effect of TK1 inhibition on tumor growth and metastasis. In this study, we performed TK1 knockdown and found that this protein is necessary for lung adenocarcinoma (LUAD) tumor growth and metastasis. Notably, inhibition of another nucleotide kinase, deoxycytidine kinase (DCK), had no effect on LUAD tumor growth and metastatic attributes. We therefore performed experiments to determine if the TK1 mechanism of action in cancer is distinct from its previously reported role in DNA damage, DNA replication, and DNA repair. We found that TK1 can promote LUAD tumor growth and metastasis in a non-canonical manner by activating Rho GTPase activity and growth and differentiation factor 15 (GDF15) expression. Taken together, our data suggest that TK1 may represent a potential target for development of LUAD therapy, due to its critical role in maintaining lung tumor growth and metastasis.