TRB2-SKP2 signaling and SKP2 targeted therapy in human retinoblastoma and related tumors

5^th World Congress on Cancer Therapy

September 28-30, 2015 Atlanta, USA

Xiaoliang X Xu1,2,3,4, Danning Hu3, Timothy Cardozo5, Yizhi Liu1, Samuel Singer3, David Cobrinik6, David H Abramson3 and Suresh C Jhanwar3

1Zhongshan Ophthalmic Center, Zhongshan University, China
2Sloan-Kettering Institute for Cancer Research, USA
3Memorial Sloan-Kettering Cancer Center, USA
4New York Eye and Ear Infirmary, USA
5New York University, USA
6T

Scientific Tracks Abstracts: J Cancer Sci Ther

Abstract :

Retinoblastomas initiate in response to biallelic RB1 inactivation and loss of functional Rb protein in cone precursors, yet the cellular circuitry that sensitizes to Rb loss have been unclear. Previous studies showed that retinoblastomas exhibit cone precursor properties and depend on cone-specific thyroid hormone receptor �²2 (TR�²2) and SKP2 signaling. Here, we show that TR�²2 promotes SKP2 expression by antagonizing TR�²1, which enables Emi1-dependent inhibition of APC/CCdh1- mediated SKP2 degradation. TR�²2 also antagonized TR�²1-mediated suppression of anterior pituitary tumors in Rb1+/- mice. Moreover, in certain RB1-wild type tumors, Rb appears to have a function similar to TR�²2, since phospho-Rb sustained Emi1 and SKP2 activity by suppressing TR�²1. While both TR�²1 and TR�²2 associated with phospho-Rb, Emi1, and SKP2, only TR�²1 suppressed SKP2 expression. These results suggest that loss of RB1, and the resulting loss of phospho-Rb, enables TR�²1-dependent suppression of Emi1 and SKP2, as a safeguard against RB1-deficient tumor formation. TR�²2 counteracts TR�²1, thus disrupting this safeguard and enabling the development of RB1-deficient tumors. SKP2-KD caused apoptosis of retinoblastoma, Rb deficient myxofibrosarcoma and small cell lung cancer cells (SCLC), indicating that SKP2 is a synthetic lethal gene in retinoblastoma and other Rb deficient cancers. Targeted therapy by SKP2 inhibitor C1 significantly suppressed retinoblastoma, SCLC, and myxofibrosarcoma tumor growth by suppressing SKP2 activity and promoting p27 accumulation in vitro and in vivo.

Biography :

Xu is a principle investigator and group leader in Zhongshan Ophthalmic Center of Zhongshan University, Basic Research Co-leader and Senior Scientist at Memorial Sloan Kettering Cancer Center (MSKCC), and Assistant Professor at New York Eye and Ear Infirmary and New York Medical College. He got MD from Zhejiang University and PhD from Shanhai Jiaotong University. His research was the key to identifying the cell of origin of retinoblastoma and to identifying a central signaling pathway for the development of this cancer; this work resulted in first-author publications in Cell, Nature, and the American Journal of Pathology.

Email: xux2@mskcc.org