Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape

Oncogenic-stress-induced senescence (OIS) is a stress response allowing normal cells, when receiving oncogenic signals, to stably arrest their proliferation. OIS thus acts to prevent aberrant cell proliferation and tumor formation. To identify novel tumor suppressive pathways, we have recently compl...

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Bibliographic Details
Published in:Oncogene 2016-03, Vol.35 (12), p.1596-1601
Main Authors: Wiel, C, Gras, B, Vindrieux, D, Warnier, M, Gitenay, D, Le Calvé, B, Ferrand, M, Augert, A, Bernard, D
Format: Article
Language:English
Subjects:
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Aging
Animals
Apoptosis
ATP Binding Cassette Transporter, Sub-Family B - physiology
Cancer
Carcinogenesis
Care and treatment
Cell Biology
Cell growth
Cell proliferation
Cells
Cells, Cultured
Cellular stress response
Chemotherapy
Drug resistance
Epithelial cells
Genetic aspects
Genetic screening
Human Genetics
Internal Medicine
Life Sciences
Medicine
Medicine & Public Health
Mice
Multidrug resistance
Multidrug resistant organisms
Neoplasms - physiopathology
Oncology
Protein expression
Proteins
Senescence
short-communication
Skin cancer
Stress response
Tumors
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Summary:Oncogenic-stress-induced senescence (OIS) is a stress response allowing normal cells, when receiving oncogenic signals, to stably arrest their proliferation. OIS thus acts to prevent aberrant cell proliferation and tumor formation. To identify novel tumor suppressive pathways, we have recently completed a loss-of-function genetic screen to identify novel genes promoting escape from OIS and thus, potentially, tumor formation when their functions are lost. Using this approach, we unexpectedly found that loss of function of the multidrug resistance protein 3 (MRP3 or ABCC3) promotes escape from OIS in human epithelial cells. Importantly, ABCC3 expression is reduced in human skin tumors, and ABCC3-knockout mice display increased sensitivity to RAS-induced skin carcinogenesis, concomitantly with decreased OIS. ABCC3 participates in resistance to chemotherapy via its transporter activity. Our data show that this transporter activity is involved in ABCC3-induced senescence, demonstrating that this protein has a complex role in cancer, since its loss of function may promote escape from OIS and tumor formation whereas its gain of function promotes resistance to chemotherapy.
ISSN:0950-9232
1476-5594
DOI:10.1038/onc.2015.218