Genipin suppresses colorectal cancer cells by inhibiting the Sonic Hedgehog pathway
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Bo Ram Kim1, Yoon A. Jeong1, Yoo Jin Na2, Seong Hye Park2, Min Jee Jo2, Jung Lim Kim1, Soyeon Jeong1, Suk-Young Lee1, Hong Jun Kim1, Sang Cheul Oh1,2 and Dae-Hee Lee1,2
1Department of Oncology, Korea University Guro Hospital, Seoul, Republic of Korea
2Graduate School of Medicine, Korea University College of Medicine, Seoul, Republic of Korea
Dae-Hee Lee, email: email@example.com
Sang Cheul Oh, email: firstname.lastname@example.org
Keywords: genipin; Hedgehog pathway; NOXA; GLI1; ubiquitin
Received: July 05, 2017 Accepted: September 04, 2017 Published: October 16, 2017
Genipin, a major component of Gardenia jasminoides Ellis fruit, has been shown to inhibit the growth of gastric, prostate, and breast cancers. However, the anti-proliferative activity of genipin in colorectal cancer (CRC) has not been characterized. Herein, we demonstrated that genipin inhibits the proliferation of CRC cells and that genipin suppressed the Hedgehog pathway. Further investigation showed that p53 and NOXA protein levels were increased during inhibition of Hedgehog pathway-mediated apoptosis in CRC cells. We also showed that p53 modulated the expression of NOXA during genipin-induced apoptosis, and suppression via SMO also played a role in this process. Subsequently, GLI1 was ubiquitinated by the E3 ligase PCAF. In a xenograft tumor model, genipin suppressed tumor growth, which was also associated with Hedgehog inactivation. Taken together, these results suggest that genipin induces apoptosis through the Hedgehog signaling pathway by suppressing p53. These findings reveal a novel regulatory mechanism involving Hedgehog/p53/NOXA signaling in the modulation of CRC cell apoptosis and tumor-forming defects.
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