Artemisia annua L. Polyphenol-Induced Cell Death Is ROS-Independently Enhanced by Inhibition of JNK in HCT116 Colorectal Cancer Cells

• Published in: International journal of molecular sciences 2021-01, Vol.22 (3), p.1366
• Main Authors: Jung, Eun Joo, Paramanantham, Anjugam, Kim, Hye Jung, Shin, Sung Chul, Kim, Gon Sup, Jung, Jin-Myung, Ryu, Chung Ho, Hong, Soon Chan, Chung, Ky Hyun, Kim, Choong Won, Lee, Won Sup
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Artemisia annua - chemistry; Artemisia annua L; cell death; Cell Death - drug effects; colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; HCT116 Cells; Humans; JNK; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - metabolism; polyphenols; Polyphenols - chemistry; Polyphenols - pharmacology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Reactive Oxygen Species - metabolism; ROS
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22031366

c-Jun N-terminal kinase (JNK) is activated by chemotherapeutic reagents including natural plant polyphenols, and cell fate is determined by activated phospho-JNK as survival or death depending on stimuli and cell types. The purpose of this study was to elucidate the role of JNK on the anticancer effects of the Korean plant L. (pKAL) polyphenols in p53 wild-type HCT116 human colorectal cancer cells. Cell morphology, protein expression levels, apoptosis/necrosis, reactive oxygen species (ROS), acidic vesicles, and granularity/DNA content were analyzed by phase-contrast microscopy; Western blot; and flow cytometry of annexin V/propidium iodide (PI)-, dichlorofluorescein (DCF)-, acridine orange (AO)-, and side scatter pulse height (SSC-H)/DNA content (PI)-stained cells. The results showed that pKAL induced morphological changes and necrosis or late apoptosis, which were associated with loss of plasma membrane/Golgi integrity, increased acidic vesicles and intracellular granularity, and decreased DNA content through downregulation of protein kinase B (Akt)/β-catenin/cyclophilin A/Golgi matrix protein 130 (GM130) and upregulation of phosphorylation of H2AX at Ser-139 (γ-H2AX)/p53/p21/Bak cleavage/phospho-JNK/p62/microtubule-associated protein 1 light chain 3B (LC3B)-I. Moreover, JNK inhibition by SP600125 enhanced ROS-independently pKAL-induced cell death through downregulation of p62 and upregulation of p53/p21/Bak cleavage despite a reduced state of DNA damage marker γ-H2AX. These findings indicate that phospho-JNK activated by pKAL inhibits p53-dependent cell death signaling and enhances DNA damage signaling, but cell fate is determined by phospho-JNK as survival rather than death in p53 wild-type HCT116 cells.