Survivin is regulated by interleukin-4 in colon cancer stem cells.
Colorectal cancer has provided an important model to test the stem cell hypothesis of cancer origin, which implies that cancer arises as a result of genetic aberrations in stem cells leading to deregulation of the proliferation/differentiation balance. We and others have demonstrated that, similarly to other solid tumors, colon carcinogenesis and progression are dictated by highly apoptosis-resistant stem-like cells. Our data have suggested that protection from apoptosis is achieved by autocrine production of interleukin-4 (IL-4) through up-regulation of anti-apoptotic mediators. In this study, we extend our analysis to another apoptosis inhibitor widely expressed in tumors, namely survivin (also known as BIRC-5, baculoviral IAP repeat-containing protein 5). We show that this protein, with important roles in cell death counteraction and mitotic progression control, is regulated by the IL-4 pathway in colon rectal cancer stem cells (CR-CSC). Hence, the presence of IL-4 increases survivin levels in our model while cytokine neutralization has opposing effects. Treatment with cytokine neutralizing agent or with leflunomide, Stat6 inhibitor, have similar consequences on survivin localization, increasing its nuclear pool, an observation known to be correlated with a good prognosis in colon cancer patients. These results demonstrate that IL-4, through activation of the STAT-6 signaling pathway, is involved in survivin expression levels as well as its localization. These findings shed more light on the molecular mechanisms involved in IL-4-mediated chemoresistance.
Di Stefano
A B
AB
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
Iovino
F
F
Lombardo
Y
Y
Eterno
V
V
Höger
T
T
Dieli
F
F
Stassi
G
G
Todaro
M
M
D000970:Antineoplastic Agents; D017209:Apoptosis / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D010766:Phosphorylation; D021381:Protein Transport; D050800:STAT6 Transcription Factor / Q000378:metabolism; D013194:Staining and Labeling; D000077022:Survivin
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; C508598:IL4 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007555:Isoxazoles; D008869:Microtubule-Associated Proteins; D009944:Organoplatinum Compounds; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D000077022:Survivin; D000077150:Oxaliplatin; D015847:Interleukin-4; D000077339:Leflunomide