The epithelial polarity regulator galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux.
Wiersma, VR; de Bruyn, M; Wei, Y; et al.van Ginkel, RJ; Hirashima, M; Niki, T; Nishi, N; Zhou, J; Pouwels, SD; Samplonius, DF; Nijman, HW; Eggleton, P; Helfrich, W; Bremer, E
Date: 18 June 2015
Journal
Autophagy
Publisher
Taylor and Francis
Publisher DOI
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 ...
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.
Institute of Biomedical & Clinical Science
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