The La protein counteracts cisplatin-induced cell death by stimulating protein synthesis of anti-apoptotic factor Bcl2

// Tilman Heise 1 , Venkatesh Kota 1 , Alexander Brock 1 , Amanda B. Morris 1 , Reycel M. Rodriguez 1 , Avery W. Zierk 1 , Philip H. Howe 1 , Gunhild Sommer 1 1 Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA Correspondence to: Gunhild Sommer, e-mail: sommerg@musc.edu Keywords: La/SSB, LARP3, RNA-binding protein, cisplatin, mRNA translation Received: November 13, 2015 Accepted: March 28, 2016 Published: April 18, 2016 ABSTRACT Up-regulation of anti-apoptotic factors is a critical mechanism of cancer cell resistance and often counteracts the success of chemotherapeutic treatment. Herein, we identified the cancer-associated RNA-binding protein La as novel factor contributing to cisplatin resistance. Our data demonstrate that depletion of the RNA-binding protein La in head and neck squamous cell carcinoma cells (HNSCC) increases the sensitivity toward cisplatin-induced cell death paralleled by reduced expression of the anti-apoptotic factor Bcl2. Furthermore, it is shown that transient expression of Bcl2 in La-depleted cells protects against cisplatin-induced cell death. By dissecting the underlying mechanism we report herein, that the La protein is required for Bcl2 protein synthesis in cisplatin-treated cells. The RNA chaperone La binds in close proximity to the authentic translation start site and unwinds a secondary structure embedding the authentic AUG. Altogether, our data support a novel model, whereby cancer-associated La protein contributes to cisplatin resistance by stimulating the translation of anti-apoptotic factor Bcl2 in HNSCC cells.