title: Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24.
abstract: Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) displays a broad range of antitumor properties including cancer-specific induction of apoptosis, inhibition of tumor angiogenesis and modulation of antitumor immune responses. In our study, we elucidated the role of MDA-7/IL-24 in inhibiting growth of breast cancer-initiating/stem cells. Ad.mda-7 infection decreased proliferation of breast cancer-initiating/stem cells without affecting normal breast stem cells. Ad.mda-7 induced apoptosis and endoplasmic reticulum stress in breast cancer-initiating/stem cells similar to unsorted breast cancer cells and inhibited the self-renewal property of breast cancer-initiating/stem cells by suppressing Wnt/β-catenin signaling. Prevention of inhibition of Wnt signaling by LiCl increased cell survival upon Ad.mda-7 treatment, suggesting that Wnt signaling inhibition might play a key role in MDA-7/IL-24-mediated death of breast cancer-initiating/stem cells. In a nude mouse subcutaneous xenograft model, Ad.mda-7 injection profoundly inhibited growth of tumors generated from breast cancer-initiating/stem cells and also exerted a potent "bystander" activity inhibiting growth of distant uninjected tumors. Further studies revealed that tumor growth inhibition by Ad.mda-7 was associated with a decrease in proliferation and angiogenesis, two intrinsic features of MDA-7/IL-24, and a reduction in vivo in the percentage of breast cancer-initiating/stem cells. Our findings demonstrate that MDA-7/IL-24 is not only nontoxic to normal cells and normal stem cells but also can kill both unsorted cancer cells and enriched populations of cancer-initiating/stem cells, providing further documentation that MDA-7/IL-24 might be a safe and effective way to eradicate cancers and also potentially establish disease-free survival.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA.
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Bhutia
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.forename: Belal
authors.initials: B
authors.lastname: Azab
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Menezes
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D018572:Disease-Free Survival; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005260:Female; D006801:Humans; D007378:Interleukins / Q000008:administration & dosage*; D061986:MCF-7 Cells; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
chemical_list: D007378:Interleukins; D000099180:Interleukin-24
keywords: MDA-7/IL-24; Wnt signaling; apoptosis; breast cancer; cancer-initiating/stem cells