Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Department of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland; Corresponding author
Ryan K. Kim
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Nikolas G. Balanis
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Caiyun Grace Li
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Rie von Eyben
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
Thomas G. Graeber
Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
Daniel Ricklin
Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland
Manuel Stucki
Department of Gynecology, University of Zurich, Wagistrasse 14, 8952 Schlieren, Switzerland
Amato J. Giaccia
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Oxford Institute of Radiation Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX37DQ, UK
Summary: The importance of innate immunity in cancer is increasingly being recognized with recent reports suggesting tumor cell-intrinsic intracellular functions for innate immunity proteins. However, such functions are often poorly understood, and it is unclear whether these are affected by patient-specific mutations. Here, we show that C4b-binding protein alpha chain (C4BPA), typically thought to reside in the extracellular space, is expressed intracellularly in cancer cells, where it interacts with the NF-κB family member RelA and regulates apoptosis. Interestingly, intracellular C4BPA expression is regulated in a stress- and mutation-dependent manner and C4BPA mutations are associated with improved cancer survival outcome. Using cell lines harboring patient-specific C4BPA mutations, we show that increasing intracellular C4BPA levels correlate with sensitivity to oxaliplatin-induced apoptosis in vitro and in vivo. Mechanistically, sensitive C4BPA mutants display increased IκBα expression and increased inhibitory IκBα-RelA complex stability. These data suggest a non-canonical intracellular role for C4BPA in regulating NF-κB-dependent apoptosis.
