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

C Wiel1,2,3,4, B Gras1,2,3,4, D Vindrieux1,2,3,4

  • 1Senescence Escape Mechanisms Laboratory, Tumoral Escape Department, Inserm U1052, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

Oncogene
|June 16, 2015
PubMed

Insights

Loss of multidrug resistance protein 3 (MRP3 or ABCC3) allows cells to escape oncogenic-stress-induced senescence (OIS), promoting tumor formation. Reduced ABCC3 expression correlates with skin tumors and increased carcinogenesis sensitivity.

Area of Science:

  • Cellular biology
  • Cancer research
  • Molecular oncology

Background:

  • Oncogenic-stress-induced senescence (OIS) is a crucial tumor suppressive mechanism preventing uncontrolled cell proliferation.
  • Identifying genes that regulate escape from OIS is vital for understanding tumor development.
  • The multidrug resistance protein 3 (MRP3 or ABCC3) is known for its role in chemotherapy resistance.

Purpose of the Study:

  • To identify novel tumor suppressive pathways by screening for genes promoting escape from OIS.
  • To investigate the role of MRP3 (ABCC3) in OIS and its implications in cancer.

Main Methods:

  • Conducted a loss-of-function genetic screen in human epithelial cells to identify genes involved in OIS escape.
  • Analyzed ABCC3 expression in human skin tumors.
  • Utilized ABCC3-knockout mouse models to study RAS-induced skin carcinogenesis and OIS.

Main Results:

  • Loss of function of MRP3 (ABCC3) unexpectedly promotes escape from OIS in human epithelial cells.
  • ABCC3 expression is significantly reduced in human skin tumors.
  • ABCC3-knockout mice exhibit increased sensitivity to RAS-induced skin carcinogenesis, with diminished OIS.
  • The transporter activity of ABCC3 is implicated in its role in senescence.

Conclusions:

  • MRP3 (ABCC3) plays a complex dual role in cancer: loss of function promotes tumor initiation by enabling escape from OIS, while its transporter activity contributes to chemotherapy resistance.
  • Reduced ABCC3 expression is a potential marker for increased skin cancer risk.
  • Targeting ABCC3 function could offer new therapeutic strategies in oncology.

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