The La protein counteracts cisplatin-induced cell death by stimulating protein synthesis of anti-apoptotic factor Bcl2.
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.
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Tilman
T
Heise
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Venkatesh
V
Kota
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Alexander
A
Brock
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Amanda B
AB
Morris
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Reycel M
RM
Rodriguez
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Avery W
AW
Zierk
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Philip H
PH
Howe
Medical University of South Carolina (MUSC), Department of Biochemistry & Molecular Biology, Charleston, SC 29425, USA.
Gunhild
G
Sommer
D000970:Antineoplastic Agents / Q000494:pharmacology; D001324:Autoantigens / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D000077195:Squamous Cell Carcinoma of Head and Neck; D015854:Up-Regulation
D000970:Antineoplastic Agents; D001324:Autoantigens; C000595707:BCL2 protein, human; C506261:SSB protein, human; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D002945:Cisplatin
LARP3; La/SSB; RNA-binding protein; cisplatin; mRNA translation