Targeting the CDK7-MDK axis to suppresses irinotecan resistance in colorectal cancer.

Autor: Huang WL; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Radiation Oncology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan., Hsu YC; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung City 824, Taiwan., Luo CW; Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan; Department of Cosmetic Science, Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan. Electronic address: 1070598@mail.kmuh.org.tw., Chang SJ; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan., Hung YH; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan., Lai CY; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan., Yang YT; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan., Chen YZ; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan., Wu CC; Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan., Chen FM; Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan., Hou MF; Division of Breast Oncology and Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan; Department of Biomedical Science and Environmental Biology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan., Pan MR; Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. Electronic address: mrpan@kmu.edu.tw.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2024 Sep 15; Vol. 353, pp. 122914. Date of Electronic Publication: 2024 Jul 14.
DOI: 10.1016/j.lfs.2024.122914
Abstrakt: Aims: Colorectal cancer (CRC) remains a major global health issue, with metastatic cases presenting poor prognosis despite advances in chemotherapy and targeted therapy. Irinotecan, a key drug for advanced CRC treatment, faces challenges owing to the development of resistance. This study aimed to understand the mechanisms underlying irinotecan resistance in colorectal cancer.
Main Methods: We created a cell line resistant to irinotecan using HT29 cells. These resistant cells were utilized to investigate the role of the CDK7-MDK axis. We employed bulk RNA sequencing, conducted in vivo experiments with mice, and analyzed patient tissues to examine the effects of the CDK7-MDK axis on the cellular response to irinotecan.
Key Findings: Our findings revealed that HT29 cells resistant to irinotecan, a crucial colorectal cancer medication, exhibited significant phenotypic and molecular alterations compared to their parental counterparts, including elevated stem cell characteristics and increased levels of cytokines and drug resistance proteins. Notably, CDK7 expression was substantially higher in these resistant cells, and targeting CDK7 effectively decreased their survival and tumor growth, enhancing irinotecan sensitivity. RNA-seq analysis indicated that suppression of CDK7 in irinotecan-resistant HT29 cells significantly reduced Midkine (MDK) expression. Decreased CDK7 and MDK levels, achieved through siRNA and the CDK7 inhibitor THZ1, enhanced the sensitivity of resistant HT29 cells to irinotecan.
Significance: Our study sheds light on how CDK7 and MDK influence irinotecan resistance in colorectal and highlights the potential of MDK-targeted therapies. We hypothesized that irinotecan sensitivity and overall treatment efficacy would improve by inhibiting MDK. This finding encourages a careful yet proactive investigation of MDK as a therapeutic target to enhance outcomes in colorectal cancer patients.
Competing Interests: Declaration of competing interest The authors declare there are no competing interests, and all authors consent to publish the data.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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