Abstract 4015: TTLL12: A promising therapeutic target for prostate cancer

Abstract

Abstract Introduction: Microtubule-targeting drugs are used for the treatment of cancer; however, they are relatively non-specific and toxic, and more specific agents need to be developed. Microtubule functional diversity is governed by posttranslational modifications, such as de-tyrosine of β-tubulin by tubulin carboxypeptidases (TCP) and re-tyrosination by TTL (tubulin tyrosine ligase). Decreased levels of de-tyrosinated tubulin and TTL are associated with increased tumour growth and poor prognosis. We have studied a protein related to TTL, Tubulin Tyrosine Ligase-Like 12 (TLL12), which we have implicated in Prostate Cancer progression and tubulin post-translational modification. Our findings open up the possibility of more specific microtubule-directed therapy, by targeting TTLL12. Links between cancer progression and TTLL12: We have shown that: • TTLL12 expression increases with prostate cancer progression and metastasis. • siRNA knockdown of endogenous TTLL12 inhibits growth of Prostate Cancer cell lines. • TTLL12 overexpression increases the number of chromosomes in karyotypically normal HCT116 cells. • The levels of TTLL12 and de-tyrosinated tubulin are higher in metastatic than normal cells. • TTLL12 is localised on de-tyrosinated tubulin filaments in cells. • TTLL12 overexpression result in resistance to traditional tubulin-targeting drugs. • TTLL12 knockout mice are cancer prone. Conclusion & Perspectives Our studies link TTLL12 to cancer progression in various ways: • TTLL12 expression increases with Prostate Cancer progression, suggesting that TTLL12 might be involved in the development of the disease. • TTLL12 overexpression affects mitosis, which is a potential link to its effects on DNA ploidy. Altered DNA ploidy is associated with cancer progression. • TTLL12 may affect cell division and mitosis through co-localisation with structures that contain tubulin. • TLL12 overexpression leads to increased tubulin de-tyrosination. Decreased tubulin tyrosination levels favour cell survival and growth, suggesting that TTLL12 may give a selective advantage to cells during cancer development by this mechanism. • TTLL12 renders cells less sensitive to tubulin-targeting drug. TTLL12 expression could be investigated as a marker for tubulin-targeted drug sensitivity and could be used to uncover mechanisms of drug response. TTL has been linked to cancer previously, and now the additional link between TTLL12 and Prostate Cancer indicates that other TTLL-family members may also be involved in cancer. Future studies of TTLL12 will be aimed at the elucidation of its mechanisms of action, its further validation as a therapeutic target and as a tumour marker, and its use to identify therapeutic molecules in high throughput screens. Acknowledgements We would like to thank for financial support the CNRS, INSERM, UdS, Procure, Prima, Cancure, ProNest FP7 ITN, INCa, Ligue Régionale contre le Cancer (CCIR-GE nO 116BL.201O). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4015. doi:1538-7445.AM2012-4015