dc.contributor.author | Wiersma, VR | |
dc.contributor.author | de Bruyn, M | |
dc.contributor.author | Wei, Y | |
dc.contributor.author | van Ginkel, RJ | |
dc.contributor.author | Hirashima, M | |
dc.contributor.author | Niki, T | |
dc.contributor.author | Nishi, N | |
dc.contributor.author | Zhou, J | |
dc.contributor.author | Pouwels, SD | |
dc.contributor.author | Samplonius, DF | |
dc.contributor.author | Nijman, HW | |
dc.contributor.author | Eggleton, P | |
dc.contributor.author | Helfrich, W | |
dc.contributor.author | Bremer, E | |
dc.date.accessioned | 2015-06-19T09:28:46Z | |
dc.date.issued | 2015-06-18 | |
dc.description.abstract | Oncogenic mutation of KRAS in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR-targeted therapy. We uncovered that KRAS mutant (KRASmut) CRC is uniquely sensitive to treatment with recombinant Galectin-9 (rGal-9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rGal-9 rapidly internalizes via clathrin- and PKC/CRAF/MEK-dependent endocytosis and accumulates in the lysosomal compartment. Treatment with rGal-9 is accompanied by activation of frustrated autophagy in KRASmut CRC, but not in BRAFmut CRC. In KRASmut CRC, rGal-9 acts as a lysosomal inhibitor that inhibits autophagosome/lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rGal-9 directly correlates with elevated basal autophagic flux in KRASmut cancer cells. Thus, rGal-9 has potent antitumor activity towards refractory KRASmut CRC cells that may be exploitable for therapeutic use. | en_GB |
dc.description.sponsorship | Dutch Cancer Society | en_GB |
dc.description.sponsorship | Netherlands Organization for Scientific Research | en_GB |
dc.description.sponsorship | Melanoma Research Alliance | en_GB |
dc.description.sponsorship | Alexander von Humboldt Foundation | en_GB |
dc.identifier.citation | Autophagy, 2015 | en_GB |
dc.identifier.doi | 10.1080/15548627.2015.1063767 | |
dc.identifier.grantnumber | RUG2009-4355 | en_GB |
dc.identifier.grantnumber | RUG2009-4542 | en_GB |
dc.identifier.grantnumber | RUG2011-5206 | en_GB |
dc.identifier.grantnumber | RUG2012-5541 | en_GB |
dc.identifier.grantnumber | RUG2013-6209 | en_GB |
dc.identifier.uri | http://hdl.handle.net/10871/17614 | |
dc.language.iso | en | en_GB |
dc.publisher | Taylor and Francis | en_GB |
dc.relation.url | http://www.tandfonline.com/doi/full/10.1080/15548627.2015.1063767 | en_GB |
dc.rights.embargoreason | Publisher's policy | en_GB |
dc.rights | © 2015 Taylor & Francis | en_GB |
dc.subject | Galectin-9 | en_GB |
dc.subject | Colon Cancer, | en_GB |
dc.subject | KRAS mutation, | en_GB |
dc.subject | Autophagy | en_GB |
dc.subject | Lysosomes | en_GB |
dc.title | The epithelial polarity regulator galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux. | en_GB |
dc.type | Article | en_GB |
dc.identifier.issn | 1554-8627 | |
dc.description | This is an Accepted Manuscript of an article published by Taylor & Francis in Autophagy on 18 June 2015, available online: http://wwww.tandfonline.com/doi/full/10.1080/15548627.2015.1063767 | en_GB |
dc.identifier.journal | Autophagy | en_GB |