Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Targeting L-type amino acid transporter 1 (LAT1) to suppress metastasis in prostate cancer (#202)

Qian Wang 1 2 , Jessamy Tiffen 1 3 , Chuck Bailey 1 3 , John Rasko 1 3 , Jeff Holst 1 2 3
  1. Centenary Institute, Newtown, NSW, Australia
  2. Origins of Cancer Laboratory, Sydney, NSW, Australia
  3. Sydney Medical School, University of Sydney, Sydney, NSW, Australia

Prostate cancer is the most common malignancy in men, and the second leading cause of male cancer-related deaths in the Western world. Approximately one in 30 men currently die from metastatic prostate cancer. The discovery of novel treatments for metastasis is a priority.  L-type amino acid transporter (LAT1; SLC7A5) transports large neutral amino acids such as leucine, in exchange for more abundant amino acids such as glutamine. We have shown that LAT1 is highly expressed after hormone ablation therapy and in metastatic prostate cancer, in order to maintain intracellular leucine levels, enabling protein synthesis and cell growth through the mTORC1 pathway. Recent studies have shown that mTOR regulates mRNA translation of genes related to cell invasion and metastasis. Therefore, LAT1 may be a novel target for therapeutic intervention in metastatic prostate cancer. LAT1 is expressed on the plasma membrane in a complex with CD98, which in turn binds 1-integrin. This complex is present at the leading edge of PC-3 cells in 2D culture. PC-3 cells adopt either an elongated or cuboidal shape in 2D culture, however LAT1 shRNA knockdown, resulted in the majority of PC-3 cells assuming a more cuboidal shape. LAT1 overexpressing cells, in contrast, maintain a more elongated shape. This result suggests that LAT1 is important in cell spreading and/or attachment, and may therefore be important in metastasis. In order to determine whether LAT1 plays a role in metastasis in vivo, we stably transduced PC-3-luc cells with a LAT1 shRNA, and used these cells in a sub-cutaneous xenograft tumour model. Knockdown of LAT1 decreased tumour growth (sub-cutaneous) as well as the numbers of metastases in the liver and lymph nodes. Our study suggests that targeting LAT1 may provide a novel therapy for metastatic prostate cancer.