Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells.

Abstract

Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.

• Authors: Arulkumar Nagappan, Won Sup Lee, Jeong Won Yun, Jing Nan Lu, Seong-Hwan Chang, Jae-Hoon Jeong, Gon Sup Kim, Jin-Myung Jung, Soon Chan Hong
• Journal: PloS one (PLoS One) Vol. 12 Issue 3 Pg. e0174591 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28355296 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Arsenicals
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Oxides
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Cyclin D1
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• p38 Mitogen-Activated Protein Kinases
• Arsenic Trioxide

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Autophagy (drug effects)
• Blotting, Western
• CDC2 Protein Kinase
• Cell Line, Tumor
• Cell Survival (drug effects)
• Colonic Neoplasms (metabolism, pathology)
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Cyclin-Dependent Kinases (metabolism)
• Dose-Response Relationship, Drug
• Enzyme Activation (drug effects)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Oxides (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Time Factors
• p38 Mitogen-Activated Protein Kinases (metabolism)