Protein Expression Profiling Identifies Key Proteins and Pathways Involved in Growth Inhibitory Effects Exerted by Guggulsterone in Human Colorectal Cancer Cells.

Leo Leo,Krishnankutty Krishnankutty,Kulinski Kulinski,Steinhoff Steinhoff,Therachiyil Therachiyil,Buddenkotte Buddenkotte,Uddin Uddin,Siveen Siveen

doi:10.3390/cancers11101478

Abstract

Colorectal cancer (CRC) is a leading killer cancer worldwide and one of the most common malignancies with increasing incidences of mortality. Guggulsterone (GS) is a plant sterol used for treatment of various ailments such as obesity, hyperlipidemia, diabetes, and arthritis. In the current study, anti-cancer effects of GS in human colorectal cancer cell line HCT 116 was tested, potential targets identified using mass spectrometry-based label-free shotgun proteomics approach and key pathways validated by proteome profiler antibody arrays. Comprehensive proteomic profiling identified 14 proteins as significantly dysregulated. Proteins involved in cell proliferation/migration, tumorigenesis, cell growth, metabolism, and DNA replication were downregulated while the protein with functional role in exocytosis/tumor suppression was found to be upregulated. Our study evidenced that GS treatment altered expression of Bcl-2 mediated the mitochondrial release of cytochrome c which triggered the formation of apoptosome as well as activation of caspase-3/7 leading to death of HCT 116 cells via intrinsic apoptosis pathway. GS treatment also induced expression of p53 protein while p21 expression was unaltered with no cell cycle arrest. In addition, GS was found to inhibit NF-kB signaling in colon cancer cells by quelling the expression of its regulated gene products Bcl-2, cIAP-1, and survivin.

Highlights

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide with a significant cause of human mortality [1,2]
11, x SW620
GS induced dose as adenocarcinoma) and SW620 were well as time-dependent inhibition proliferation both cell lines while, viable cells treated with increasing dosesof of cell 24 h and 48 hin and cell the viability was determined by MTT

Summary

Introduction

Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide with a significant cause of human mortality [1,2]. Cancers 2019, 11, 1478 still remains challenging as non-specificity of chemotherapeutics by targeting tumor specific cells and, non-malignant cells can result in many side effects, eventually leading to multi-drug resistance. This kind of cytotoxic therapy can impair the quality of patient’s life and undesirably affect the course, outcome as well as costs of the treatment. Complementary and alternative medicines that serve as better therapeutics which could significantly improve the management of colorectal cancer are in demand. Natural compounds (phytochemicals), the biologically active substances derived from plants, hold great potential for medicinal applications even in cancer therapeutics

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