Open AccessAngiopoietin‐like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase–phosphoinositide 3‐kinase‐dependent anti‐apoptotic signaling
Author(s) -
Horiguchi Haruki,
Endo Motoyoshi,
Miyamoto Yuji,
Sakamoto Yasuo,
Odagiri Haruki,
Masuda Tetsuro,
Kadomatsu Tsuyoshi,
Tanoue Hironori,
Motokawa Ikuyo,
Terada Kazutoyo,
Morioka Masaki Suimye,
Manabe Ichiro,
Baba Hideo,
Oike Yuichi
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12554
Subject(s) - cancer research , angiogenesis , syk , metastasis , apoptosis , signal transduction , pi3k/akt/mtor pathway , carcinogenesis , medicine , tyrosine kinase , cancer , biology , microbiology and biotechnology , biochemistry
Angiopoietin‐like protein 2 ( ANGPTL 2) plays an important role in inflammatory carcinogenesis and tumor metastasis by activating tumor angiogenesis and tumor cell chemotaxis and invasiveness. However, it is unclear whether ANGPTL 2 expression has an effect on tumor cell survival. Here, we explored that possibility by determining whether ANGPTL 2 expression altered survival of human colorectal cancer cell lines treated with antineoplastic drugs. To do so, we generated SW 480 cells expressing ANGPTL 2 ( SW 480/ ANGPTL 2) and control ( SW 480/ C trl) cells. Apoptosis induced by antineoplastic drug treatment was significantly decreased in SW 480/ ANGPTL 2 compared to control cells. Expression of anti‐apoptotic BCL ‐2 family genes was upregulated in SW 480/ ANGPTL 2 compared to SW 480/ C trl cells. To assess signaling downstream of ANGPTL 2 underlying this effect, we carried out RNA sequencing analysis of SW 480/ ANGPTL 2 and SW 480/ C trl cells. That analysis, combined with in vitro experiments, indicated that S yk‐ PI 3 K signaling induced expression of BCL ‐2 family genes in SW 480/ ANGPTL 2 cells. Furthermore, ANGPTL 2 increased its own expression in a feedback loop by activating the spleen tyrosine kinase–nuclear factor of activated T cells ( S yk– NFAT ) pathway. Finally, we observed a correlation between higher ANGPTL 2 expression in primary unresectable tumors from colorectal cancer patients who underwent chemotherapy with a lower objective response rate. These findings suggest that attenuating ANGPTL 2 signaling in tumor cells may block tumor cell resistance to antineoplastic therapies.