EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity.
EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR/EGFRvIII-expressing glioblastoma cells to Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR/EGFRvIII that leads to tumor drug resistance.
Department of Surgery, Divisions of Surgical Sciences and Neurosurgery, Duke University School of Medicine, 103 Research Drive, Durham, NC 27710, USA.
Hu
H
Zhu
Xinyu
X
Cao
Francis
F
Ali-Osman
Stephen
S
Keir
Hui-Wen
HW
Lo
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004251:DNA Transposable Elements; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D014644:Genetic Variation; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D017384:Sequence Deletion; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D004251:DNA Transposable Elements; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors; D000077156:Gefitinib