RRC ID 78173
Author Tamura S, Tazawa H, Hori N, Li Y, Yamada M, Kikuchi S, Kuroda S, Urata Y, Kagawa S, Fujiwara T.
Title p53-armed oncolytic adenovirus induces autophagy and apoptosis in KRAS and BRAF-mutant colorectal cancer cells.
Journal PLoS One
Abstract Colorectal cancer (CRC) cells harboring KRAS or BRAF mutations show a more-malignant phenotype than cells with wild-type KRAS and BRAF. KRAS/BRAF-wild-type CRCs are sensitive to epidermal growth factor receptor (EGFR)-targeting agents, whereas KRAS/BRAF-mutant CRCs are resistant due to constitutive activation of the EGFR-downstream KRAS/BRAF signaling pathway. Novel therapeutic strategies to treat KRAS/BRAF mutant CRC cells are thus needed. We recently demonstrated that the telomerase-specific replication-competent oncolytic adenoviruses OBP-301 and p53-armed OBP-702 exhibit therapeutic potential against KRAS-mutant human pancreatic cancer cells. In this study, we evaluated the therapeutic potential of OBP-301 and OBP-702 against human CRC cells with differing KRAS/BRAF status. Human CRC cells with wild-type KRAS/BRAF (SW48, Colo320DM, CACO-2), mutant KRAS (DLD-1, SW620, HCT116), and mutant BRAF (RKO, HT29, COLO205) were used in this study. The antitumor effect of OBP-301 and OBP-702 against CRC cells was analyzed using the XTT assay. Virus-mediated modulation of apoptosis, autophagy, and the EGFR-MEK-ERK and AKT-mTOR signaling pathways was analyzed by Western blotting. Wild-type and KRAS-mutant CRC cells were sensitive to OBP-301 and OBP-702, whereas BRAF-mutant CRC cells were sensitive to OBP-702 but resistant to OBP-301. Western blot analysis demonstrated that OBP-301 induced autophagy and that OBP-702 induced autophagy and apoptosis in human CRC cells. In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.
Volume 18(11)
Pages e0294491
Published 2023-1-1
DOI 10.1371/journal.pone.0294491
PII PONE-D-23-29831
PMID 37972012
PMC PMC10653454
MeSH Adenoviridae / genetics Adenoviridae / metabolism Apoptosis / genetics Autophagy / genetics Caco-2 Cells Cell Line, Tumor Colorectal Neoplasms* / drug therapy Colorectal Neoplasms* / therapy ErbB Receptors / genetics ErbB Receptors / metabolism Humans Mitogen-Activated Protein Kinase Kinases / metabolism Mutation Proto-Oncogene Proteins B-raf* / genetics Proto-Oncogene Proteins B-raf* / metabolism Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins p21(ras) / genetics Proto-Oncogene Proteins p21(ras) / metabolism TOR Serine-Threonine Kinases / metabolism Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism
Human and Animal Cells CACO-2(RCB0988) COLO205(RCB2127)