A novel role of gap junction connexin46 protein to protect breast tumors from hypoxia.
Connexin proteins are the principle structural components of the gap junctions. Colocalization and tissue-specific expression of diverse connexin molecules are reported to occur in a variety of organs. Impairment of gap junctional intercellular communication, caused by mutations, gain of function or loss of function of connexins, is involved in a number of diseases including the development of cancer. Here we show that human breast cancer cells, MCF-7 and breast tumor tissues express a novel gap junction protein, connexin46 (Cx46) and it plays a critical role in hypoxia. Previous studies have shown that connexin46 is predominantly expressed in lens and our studies find that Cx46 protects human lens epithelial cells from hypoxia induced death. Interestingly, we find that Cx46 is upregulated in MCF-7 breast cancer cells and human breast cancer tumors. Downregulation of Cx46 by siRNA promotes 40% MCF-7 cell death at 24 hr under hypoxic conditions. Furthermore, direct injection of anti-Cx46 siRNA into xenograft tumors prevents tumor growth in nude mice. This finding will provide an exciting new direction for drug development for breast cancer treatment and suggests that both normal hypoxic tissue (lens) and adaptive hypoxic tissue (breast tumor) utilize the same protein, Cx46, as a protective strategy from hypoxia.
Banerjee
Debarshi
D
Department of Biochemistry, Kansas State University, Manhattan, KS, USA. debarshi@ksu.edu
Gakhar
Gunjan
G
Madgwick
Dan
D
Hurt
Amy
A
Takemoto
Dolores
D
Nguyen
Thu Annelise
TA
D000328:Adult; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D049109:Cell Proliferation; D002470:Cell Survival; D017630:Connexins / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D017629:Gap Junctions; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007908:Lens, Crystalline / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
D017630:Connexins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C082917:GJA3 protein, human