β-Lapachone Exerts Anticancer Effects by Downregulating p53, Lys-Acetylated Proteins, TrkA, p38 MAPK, SOD1, Caspase-2, CD44 and NPM in Oxaliplatin-Resistant HCT116 Colorectal Cancer Cells.

Abstract

β-lapachone (β-Lap), a topoisomerase inhibitor, is a naturally occurring ortho-naphthoquinone phytochemical and is involved in drug resistance mechanisms. Oxaliplatin (OxPt) is a commonly used chemotherapeutic drug for metastatic colorectal cancer, and OxPt-induced drug resistance remains to be solved to increase chances of successful therapy. To reveal the novel role of β-Lap associated with OxPt resistance, 5 μM OxPt-resistant HCT116 cells (HCT116-OxPt-R) were generated and characterized via hematoxylin staining, a CCK-8 assay and Western blot analysis. HCT116-OxPt-R cells were shown to have OxPt-specific resistance, increased aggresomes, upregulated p53 and downregulated caspase-9 and XIAP. Through signaling explorer antibody array, nucleophosmin (NPM), CD37, Nkx-2.5, SOD1, H2B, calreticulin, p38 MAPK, caspase-2, cadherin-9, MMP23B, ACOT2, Lys-acetylated proteins, COL3A1, TrkA, MPS-1, CD44, ITGA5, claudin-3, parkin and ACTG2 were identified as OxPt-R-related proteins due to a more than two-fold alteration in protein status. Gene ontology analysis suggested that TrkA, Nkx-2.5 and SOD1 were related to certain aggresomes produced in HCT116-OxPt-R cells. Moreover, β-Lap exerted more cytotoxicity and morphological changes in HCT116-OxPt-R cells than in HCT116 cells through the downregulation of p53, Lys-acetylated proteins, TrkA, p38 MAPK, SOD1, caspase-2, CD44 and NPM. Our results indicate that β-Lap could be used as an alternative drug to overcome the upregulated p53-containing OxPt-R caused by various OxPt-containing chemotherapies.

• Authors: Eun Joo Jung, Hye Jung Kim, Sung Chul Shin, Gon Sup Kim, Jin-Myung Jung, Soon Chan Hong, Choong Won Kim, Won Sup Lee
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 12 (Jun 07 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37373014 (Publication Type: Journal Article)

Chemical References

• Oxaliplatin
• Tumor Suppressor Protein p53
• beta-lapachone
• Superoxide Dismutase-1
• Caspase 2
• p38 Mitogen-Activated Protein Kinases
• Nucleophosmin
• Receptor Protein-Tyrosine Kinases
• CD44 protein, human
• Hyaluronan Receptors
• SOD1 protein, human

Topics

• Humans
• Oxaliplatin (pharmacology, therapeutic use)
• HCT116 Cells
• Tumor Suppressor Protein p53 (metabolism)
• Superoxide Dismutase-1 (metabolism)
• Colorectal Neoplasms (pathology)
• Caspase 2 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)
• Nucleophosmin
• Receptor Protein-Tyrosine Kinases (metabolism)
• Apoptosis
• Cell Line, Tumor
• Hyaluronan Receptors (metabolism)