Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.
Highlights
Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the world [1]
We demonstrated that Dragon expression increased in colon cancers, especially in those at advanced stages, compared with control tissues, and that Dragon promoted colon cancer cell proliferation in vitro and CRC progression in vivo [18]
We discovered another important role for Dragon in the inhibitions of oxaliplatin-induced CRC cell apoptosis and the subsequent resistance of CRC cells to oxaliplatin treatment
Summary
Colorectal cancer (CRC) is the second leading cause of cancer-associated mortality in the world [1]. Epidermal growth factor receptor (EGFR) targeting has been used to treat advanced colon cancer [6, 7], and an antiinterleukin-6 (IL-6) receptor antibody has been used to suppress angiogenesis and inhibit CRC growth [8]. On the other hand, oxaliplatinbased chemotherapy is still the standard adjuvant therapy for advanced CRC and a first-line treatment option in cases of metastasis. The current systemic treatment for CRC includes oxaliplatin or irinotecan combined with 5-fluorouracil (5-FU) [11]. As a single agent, oxaliplatin has been found to be less effective against transforming cancerous cells, and the acquisition www.impactjournals.com/oncotarget of drug resistance remains a major stumbling block [12]. The molecular mechanisms underlying oxaliplatin resistance following CRC chemotherapy are poorly understood, and deserve further investigation
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