title: An ornamental plant targets epigenetic signaling to block cancer stem cell-driven colon carcinogenesis.
abstract: Phytochemicals modulate key cellular signaling pathways and have proven anticancer effects. Alcea rosea(AR; Hollyhock) is an ornamental plant with known anti-inflammatory properties. This study explored its role as an anticancer agent. The AR seed extract (AR extract) inhibited proliferation and colony formation in a dose- and time-dependent manner and promoted apoptosis as was evidenced by cleavage of PARP and increased expression of Bax accompanying reduced levels of BCL-xl protein in HCT116 and SW480 cells, respectively. In addition, AR extract-arrested cells at Go/G1 phase of cell cycle and exhibited decreases in Cyclin D1. AR extract-treated cells exhibited reduced number and size of colonospheres in a dose-dependent manner concomitant with decreases in cancer stem cell (CSC) markers ALDH1A1 and Dclk1. Relative levels of β-catenin, Notch-ICD, Hes1 and EZH2 were also attenuated by AR extract. TOP-flash reporter activity, a measure of Wnt signaling, decreased significantly in response to treatment while overexpression of wild type but not mutant EZH2, reversed the inhibitory effects. Moreover, WIF1 (a Wnt antagonist) promoter activity increased dramatically following treatment with AR extract which phenocopied increases in WIF1 reporter activity following EZH2 knockdown.In vivo, AR extract attenuated tumor growth due probably to reduced levels of EZH2, β-catenin, CyclinD1 and Ki-67 along with reduced levels of CSC markers. Since partial purification via HPLC yielded a prominent peak, efforts are underway to identify the active ingredient(s). Taken together, the results clearly suggest that AR extract/active component(s) can be an effective preventative/therapeutic agent to target colon cancer.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Ishfaq
authors.initials: I
authors.lastname: Ahmed
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Badal C
authors.initials: BC
authors.lastname: Roy
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Dharmalingam
authors.initials: D
authors.lastname: Subramaniam
authors.affiliation: Department of Biochemistry, University of Kashmir, Srinagar 190006, India.
authors.forename: Showkat Ahmad
authors.initials: SA
authors.lastname: Ganie
authors.affiliation: Center for Drug Evaluation and Research, US Food and Drug Adminstration, Silver Spring, MD 20993, USA.
authors.forename: Deep
authors.initials: D
authors.lastname: Kwatra
authors.affiliation: Department of Cancer Biology and.
authors.forename: Dan
authors.initials: D
authors.lastname: Dixon
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA, University of Kansas Cancer Center, Kansas City, KS 66160, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.affiliation: Department of Biochemistry, University of Kashmir, Srinagar 190006, India.
authors.forename: Mohammad Afzal
authors.initials: MA
authors.lastname: Zargar
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA, University of Kansas Cancer Center, Kansas City, KS 66160, USA sumar@kumc.edu.
authors.forename: Shahid
authors.initials: S
authors.lastname: Umar
mesh_terms: D003110:Colonic Neoplasms / Q000473:pathology*; D044127:Epigenesis, Genetic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010944:Plants; D015398:Signal Transduction