Stress-resistant translation of cathepsin L mRNA in breast cancer rogression
08.05.2015
Tholen M, Wolanski J, Stolze B, Chiabudini M, Gajda M, Bronsert P, Stickeler E, Rospert S, Reinheckel T.
J Biol Chem. 2015;290(25):15758-69.
The cysteine protease cathepsin L (CTSL) is often thought to act as a tumor promoter by enhancing tumor progression and metastasis. This goes along with increased CTSL activity in various tumor tissues; however, the mechanisms leading to high CTSL levels are incompletely understood. With the help of a breast cancer mouse model additionally expressing a human CTSL genomic transgene, we show that CTSL indeed promotes breast cancer metastasis to the lung. During tumor formation and progression high expression levels of CTSL are maintained by enduring translation of CTSL mRNA. By polyribosome profiling of tissues and cells, we observe an intrinsic resistance of CTSL to stress-induced shut down of translation. This ability can be attributed to all 5UTR variants of CTSL and is not dependent on a previously described IRES motif. In conclusion, we provide in vivo functional evidence for overexpressed CTSL as a promoter of lung metastasis, while high CTSL levels are maintained during tumor progression due to stress-resistant mRNA translation.
