Flavopereirine Suppresses the Growth of Colorectal Cancer Cells through P53 Signaling Dependence.

Jhy-Ming Li,Chung-Sheng Shi,Chih-Chung Cheng,Shun-Fu Chang,Yun-Ching Huang,Ying-Ray Lee,Chih-Chien Chin,Yi-Hung Kuo,Feng-Che Kuan

doi:10.3390/cancers11071034

Abstract

Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. The outcome of CRC patients remains poor. Thus, a new strategy for CRC treatment is urgently needed. Flavopereirine is a β-carboline alkaloid extracted from Geissospermum vellosii, which can reduce the viability of various cancer cells through an unknown mode of action. The aim of the present study was to investigate the functional mechanism and therapeutic potential of flavopereirine on CRC cells in vitro and in vivo. Our data showed that flavopereirine significantly lowered cellular viability, caused intrinsic and extrinsic apoptosis, and induced G2/M-phase cell cycle arrest in CRC cells. Flavopereirine downregulated Janus kinases-signal transducers and activators of transcription (JAKs-STATs) and cellular myelocytomatosis (c-Myc) signaling in CRC cells. In contrast, the enforced expressions of constitutive active STAT3 and c-Myc could not restore flavopereirine-induced viability reduction. Moreover, flavopereirine enhanced P53 expression and phosphorylation in CRC cells. CRC cells with P53 knockout or loss-of-function mutation significantly diminished flavopereirine-mediated viability reduction, indicating that P53 activity plays a major role in flavopereirine-mediated CRC cell growth suppression. Flavopereirine also significantly repressed CRC cell xenograft growth in vivo by upregulating P53 and P21 and inducing apoptosis. In conclusion, flavopereirine-mediated growth suppression in CRC cells depended on the P53-P21, but not the JAKs-STATs-c-Myc signaling pathway. The present study suggests that flavopereirine may be efficacious in the clinical treatment of CRC harboring functional P53 signaling.

Highlights

High-grade colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide [1].Though advances have been made in current therapeutic approaches, their benefits are limited in clinical practice [2,3]
We investigated the effects of flavopereirine on the viability of various malignant stages of the Colorectal cancer (CRC) cell lines SW1116 (Duke’s stage A), SW480 (Duke’s stage B), DLD1, SW620 (Duke’s stage C), HCT116 (Duke’s stage D), and HT29
As flavopereirine reduced the viability of certain malignant CRC cells, we examined the apoptotic effect of flavopereirine on the most sensitive cell lines

Summary

Introduction

High-grade colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide [1].Though advances have been made in current therapeutic approaches, their benefits are limited in clinical practice [2,3]. Risk factors in CRC development include the influences of early-stage adenomatous polyposis coli (APC) mutations [6] and late-stage tumor suppressor p53 and K-ras mutations on malignant epithelial-mesenchymal phenotype transformation [7]. Various signaling pathways such as Janus kinases-signal transducers and activators of transcription (JAKs-STATs) participate in CRC progression [8]. The four mammalian JAK family members are JAK1, JAK2, JAK3, and Tyrosine Kinase 2 They selectively phosphorylate and activate STATs [10]. It regulates B-cell lymphoma 2 (Bcl-2), Myeloid cell leukemia-1 (Mcl-1), and cellular myelocytomatosis (c-Myc) expression to maintain cell survival and proliferation [15,16]

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Conclusion