Synuclein γ Compromises Spindle Assembly Checkpoint and Renders Resistance to Antimicrotubule Drugs

Abstract

Defects in the spindle assembly checkpoint (SAC) have been proposed to contribute to the chromosomal instability in human cancers. One of the major mechanisms underlying antimicrotubule drug (AMD) resistance involves acquired inactivation of SAC. Synuclein g (SNCG), previously identified as a breast cancer-specific gene, is highly expressed in malignant cancer cells but not in normal epithelium. Here, we show that SNCG is sufficient to induce resistance to AMD-caused apoptosis in breast cancer cells and cancer xenografts. SNCG binds to spindle checkpoint kinase BubR1 and inhibits its kinase activity. Specifically, the C-terminal (Gln106-Asp127) of SNCG binds to the N-terminal TPR (tetratricopeptidelike folds) motif of BubR1. SNCG-BubR1 interaction induces a structure change of BubR1, attenuates its interaction with other key checkpoint proteins of Cdc20, and thus compromises SAC function. SNCG expression in breast cancers from patients with a neoadjuvant clinical trial showed that SNCG-positive tumors are resistant to chemotherapy-induced apoptosis. These data show that SNCG renders AMD resistance by inhibiting BubR1 activity and attenuating SAC function. Mol Cancer Ther; 13(3); 699-713. Ó2014 AACR.

Metastasis regulation by PPARD expression in cancer cells

“…SNCG is a small soluble protein that interferes with the normal mitotic checkpoint and forms a positive feedback loop with insulin-like growth factor signaling (58). SNCG promotes tumor invasion, metastasis, and resistance to antineoplastic-induced apoptosis (58)(59)(60). SNCG expression is upregulated in several common human cancers (e.g., lung, breast, prostate, colon) and is correlated with metastasis risk (61)(62)(63).…”

Cdc20: At the Crossroads between Chromosome Segregation and Mitotic Exit

“…Such findings stimulated the search for and development of inhibitors that target the catalytic site of the SAC kinases Aurora B and Mps1, some of which have entered clinical trials. Examples are: the Aurora kinase inhibitor AT9283, which is prescribed for the treatment of non-Hodgkin's lymphoma (Phase I completed; NCT00443976); the inhibitor PF-03814735, which is used for the treatment of histologically or cytologically confirmed malignancies (Phase I completed; NCT00424632); and the Mps1 inhibitor BAY1161909 (in Phase I trial for the treatment of solid tumours; NCT02138812) [66,67]. Unfortunately, the use of smallsized inhibitors that act as ATP-binding competitors, including those that target SAC kinases, has been of limited success.…”

Synuclein‐γ in uterine serous carcinoma impacts survival: An NRG Oncology/Gynecologic Oncology Group study

“…It was demonstrated that SNCG binds to a spindle checkpoint kinase, BUB1B, thereby inducing a structural change in BUB1B. This inhibited its kinase activity and attenuated its interaction with other key checkpoint proteins, such as cell‐division cycle protein 20 (Cdc20), compromising the spindle assembly checkpoint . The lack of checkpoint function would allow cells to override G2/M arrest with aneuploidy proliferation to perpetuate genomic instability.…”

“…This inhibited its kinase activity and attenuated its interaction with other key checkpoint proteins, such as cell-division cycle protein 20 (Cdc20), compromising the spindle assembly checkpoint. 16,24,25 The lack of checkpoint function would allow cells to override G2/M arrest with aneuploidy proliferation to perpetuate genomic instability. By targeting SNCG with a specific peptide, sensitivity to paclitaxel was enhanced.…”