Synuclein-gamma targeting peptide inhibitor that enhances sensitivity of breast cancer cells to antimicrotubule drugs

Vinay K Singh, Yue Zhou, Joseph A Marsh, Vladimir N Uversky, Julie D Forman-Kay, Jingwen Liu, Zongchao Jia

Research output: Contribution to journalArticlepeer-review

Abstract

Synuclein-gamma (SNCG) plays oncogenic roles in breast carcinogenesis. Although the expression of SNCG is abnormally high in advanced and metastatic breast carcinomas, SNCG is not expressed in normal or benign breast tissues. SNCG is an intrinsically disordered protein known to interact with BubR1, a mitotic checkpoint kinase. The SNCG-BubR1 interaction inhibits mitotic checkpoint control upon spindle damage caused by anticancer drugs, such as nocodazole and taxol. Antimicrotubule drugs that cause mitotic arrest and subsequent apoptosis of cancer cells are frequently used to treat breast cancer patients with advanced or metastatic diseases. However, patient response rates to this class of chemotherapeutic agents vary significantly. In this study, we have designed a novel peptide (ANK) and shown its interaction with SNCG using fluorometry, surface plasmon resonance, and isothermal titration calorimetry. Binding of the ANK peptide did not induce folding of SNCG, suggesting that SNCG can function biologically in its intrinsically disordered state. Microinjection of the ANK peptide in breast cancer cell line overexpressing SNCG (MCF7-SNCG) exhibited a similar cell killing response by nocodazole as in the SNCG-negative MCF7 cells. Overexpression of enhanced green fluorescent protein-tagged ANK reduces SNCG-mediated resistance to paclitaxel treatment by approximately 3.5-fold. Our coimmunoprecipitation and colocalization results confirmed the intracellular association of the ANK peptide with SNCG. This is likely due to the disruption of the interaction of SNCG with BubR1 interaction. Our findings shed light on the molecular mechanism of the ANK peptide in releasing SNCG-mediated drug resistance.
Original languageEnglish
Pages (from-to)626-33
Number of pages8
JournalCancer Research
Volume67
Issue number2
DOIs
Publication statusPublished - 15 Jan 2007

Keywords

  • Amino Acid Sequence
  • Animals
  • Ankyrins
  • Antineoplastic Agents
  • Breast Neoplasms
  • COS Cells
  • Cell Line, Tumor
  • Cercopithecus aethiops
  • Conserved Sequence
  • Drug Resistance, Neoplasm
  • Humans
  • Kinetics
  • Microtubules
  • Mitosis
  • Molecular Sequence Data
  • Neoplasm Proteins
  • Nocodazole
  • Peptide Fragments
  • Protein Folding
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • gamma-Synuclein

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