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Daunorubicin induces GLI1‑dependent apoptosis in colorectal cancer cell lines
Bo Ram Kim1, Dae Yeong Kim1, Na Ly Tran2
1Division of Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
Abstract:
Daunorubicin, also known as daunomycin, is a DNA‑targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to have anticancer effects in monotherapy or combination therapy in solid tumors, but at present it has not been adequately studied in colorectal cancer (CRC). In the present study, from a screening using an FDA‑approved drug library, it was found that daunorubicin suppresses GLI‑dependent luciferase reporter activity. Daunorubicin also increased p53 levels, which contributed to both GLI1 suppression and apoptosis. The current detailed investigation showed that daunorubicin promoted the β‑TrCP‑mediated ubiquitination and proteasomal degradation of GLI1. Moreover, a competition experiment using BODIPY‑cyclopamine, a well‑known Smo inhibitor, suggested that daunorubicin does not bind to Smo in HCT116 cells. Administration of daunorubicin (2 mg/kg, ip, qod, 15 days) into HCT116 xenograft mice profoundly suppressed tumor progress and the GLI1 level in tumor tissues. Taken together, the present results revealed that daunorubicin suppresses canonical Hedgehog pathways in CRC. Ultimately, the present study discloses a new mechanism of daunorubicin's anticancer effect and might provide a rationale for expanding the clinical application of daunorubicin.
Insights
Daunorubicin, an anticancer drug, effectively suppresses colorectal cancer progression by targeting the GLI1 protein. This study reveals a new mechanism for its anticancer effects, potentially expanding its clinical use.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Daunorubicin is a chemotherapy agent primarily for leukemia.
- Its efficacy in solid tumors, including colorectal cancer (CRC), is understudied.
- The canonical Hedgehog pathway is implicated in CRC development.
Purpose of the Study:
- To investigate daunorubicin's effect on colorectal cancer.
- To elucidate the molecular mechanisms underlying daunorubicin's anticancer activity in CRC.
- To explore the potential of daunorubicin in CRC treatment.
Main Methods:
- Screening of an FDA-approved drug library.
- Assessing GLI-dependent luciferase reporter activity.
- Western blot analysis for p53 and GLI1 levels.
- Ubiquitination and proteasomal degradation assays.
- In vivo studies using HCT116 xenograft mouse models.
Main Results:
- Daunorubicin suppressed GLI-dependent reporter activity in CRC cells.
- It increased p53 levels, leading to GLI1 suppression and apoptosis.
- Daunorubicin induced β‑TrCP-mediated degradation of GLI1.
- Daunorubicin did not bind to Smo in HCT116 cells.
- In vivo, daunorubicin significantly inhibited tumor growth and reduced GLI1 levels.
Conclusions:
- Daunorubicin effectively suppresses the canonical Hedgehog pathway in colorectal cancer.
- It acts through p53-mediated GLI1 degradation.
- This study provides a novel mechanism for daunorubicin's anticancer effects and suggests its potential for CRC treatment expansion.
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