Up‐regulated EGF receptors undergo to rapid internalization and ubiquitin‐dependent degradation in human cancer cells exposed to 8‐Cl‐cAMP

FEBS Letters

Abbruzzese, A.³  Barbarulo, D.²  Di Gennaro, E.²  Marra, M.³  Caraglia, M.³  Budillon, A.²  Tagliaferri, P.¹ 

[1] Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università degli Studi di Napoli ‘Federico II’, Naples, Italy;Istituto dei Tumori di Napoli, Fondazione ‘G. Pascale’, via Mariano Semmola, 80131 Naples, Italy;Dipartimento di Biochimica e Biofisica, II Università di Napoli, Naples, Italy

关键词: cAMP analogue;    Protein kinase A;    Epidermal growth factor receptor;    Endocytosis;    Ubiquitin;    Mitogen-activated protein kinase;    EGF;    epidermal growth factor;    EGF-R;    EGF receptor;    MAPK;    mitogen-activated protein kinase;    PKA;    cAMP-dependent protein kinase;    MAb;    monoclonal antibody;    IFNα;    α2-recombinant interferon;    PGF-R;    peptide growth factor receptor;   

DOI  :  10.1016/S0014-5793(99)00292-6

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

8-Cl-cAMP, a cAMP analogue that antagonizes type I cAMP-dependent protein kinase, is a novel anti-tumor agent presently under investigation in clinical trials. Herein we report the effects of this agent on epidermal growth factor receptor expression and degradation in human KB cancer cells. Exposure to 10 μM 8-Cl-cAMP for 48 h induced a 65% increase in epidermal growth factor receptor surface expression while the receptor synthesis was 22-fold enhanced. Analysis of epidermal growth factor-dependent receptor internalization in 8-Cl-cAMP-treated cells showed a higher endocytosis rate as well as an accelerated degradation which occurred together with an increased receptor ubiquitination. The enhanced degradation of epidermal growth factor receptor correlated with the lack of epidermal growth factor-induced proliferation and mitogen-activated protein kinase stimulation. The disregulation of epidermal growth factor receptor internalization and ubiquitin-dependent degradation could underlay a new mechanism of the anti-tumor activity of 8-Cl-cAMP suggesting its combination with agents that disrupt epidermal growth factor receptor signalling.

【 授权许可】

Unknown