5th World Congress on Cancer Therapy
Zhongshan University, China
Title: TRB2-SKP2 signaling and SKP2 targeted therapy in human retinoblastoma and related tumors
Biography: Xiaoliang X. Xu
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-specifi c thyroid hormone receptor 2 (TR2) and SKP2 signaling. Here, we show that TR2 promotes SKP2 expression by antagonizing TR1, which enables Emi1-dependent inhibition of APC/CCdh1- mediated SKP2 degradation. TR2 also antagonized TR1-mediated suppression of anterior pituitary tumors in Rb1+/- mice. Moreover, in certain RB1-wild type tumors, Rb appears to have a function similar to TR2, since phospho-Rb sustained Emi1 and SKP2 activity by suppressing TR1. While both TR1 and TR2 associated with phospho-Rb, Emi1, and SKP2, only TR1 suppressed SKP2 expression. Th ese results suggest that loss of RB1, and the resulting loss of phospho-Rb, enables TR1-dependent suppression of Emi1 and SKP2, as a safeguard against RB1-defi cient tumor formation. TR2 counteracts TR1, thus disrupting this safeguard and enabling the development of RB1-defi cient tumors. SKP2-KD caused apoptosis of retinoblastoma, Rb defi cient myxofi brosarcoma and small cell lung cancer cells (SCLC), indicating that SKP2 is a synthetic lethal gene in retinoblastoma and other Rb defi cient cancers. Targeted therapy by SKP2 inhibitor C1 signifi cantly suppressed retinoblastoma, SCLC, and myxofi brosarcoma tumor growth by suppressing SKP2 activity and promoting p27 accumulation in vitro and in vivo.