The epithelial polarity regulator LGALS9/galectin-9 induces fatal frustrated autophagy in KRAS mutant colon carcinoma that depends on elevated basal autophagic flux.
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| Abstract |
Oncogenic mutation of KRAS (Kirsten rat sarcoma viral oncogene homolog) in colorectal cancer (CRC) confers resistance to both chemotherapy and EGFR (epidermal growth factor receptor)-targeted therapy. We uncovered that KRAS mutant (KRAS(mut)) CRC is uniquely sensitive to treatment with recombinant LGALS9/Galectin-9 (rLGALS9), a recently established regulator of epithelial polarity. Upon treatment of CRC cells, rLGALS9 rapidly internalizes via early- and late-endosomes and accumulates in the lysosomal compartment. Treatment with rLGALS9 is accompanied by induction of frustrated autophagy in KRAS(mut) CRC, but not in CRC with BRAF (B-Raf proto-oncogene, serine/threonine kinase) mutations (BRAF(mut)). In KRAS(mut) CRC, rLGALS9 acts as a lysosomal inhibitor that inhibits autophagosome-lysosome fusion, leading to autophagosome accumulation, excessive lysosomal swelling and cell death. This antitumor activity of rLGALS9 directly correlates with elevated basal autophagic flux in KRAS(mut) cancer cells. Thus, rLGALS9 has potent antitumor activity toward refractory KRAS(mut) CRC cells that may be exploitable for therapeutic use.
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| Authors | Valerie R Wiersma, Marco de Bruyn, Yunwei Wei, Robert J van Ginkel, Mitsuomi Hirashima, Toshiro Niki, Nozomu Nishi, Jin Zhou, Simon D Pouwels, Douwe F Samplonius, Hans W Nijman, Paul Eggleton, Wijnand Helfrich, Edwin Bremer |
| Journal | Autophagy (Autophagy) Vol. 11 Issue 8 Pg. 1373-88 ( 2015) ISSN: 1554-8635 [Electronic] United States |
| PMID | 26086204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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