Research Paper Volume 12, Issue 9 pp 8067—8083
BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways
- 1 INSERM, UMR935, Malignant and Therapeutic Stem Cells Models, Villejuif, France
- 2 Paris-Saclay University, Saint-Aubin, France
- 3 INSERM, UMR1197 Interactions between Stem Cells and Their Niches in Physiology, Tumors and Tissue Repair, Villejuif, France
- 4 Hôpital Paul Brousse AP-HP, Villejuif, France
- 5 Sorbonne Université and CNRS, Institut de Biologie Paris Seine, UMR8256 Biological Adaptation and Aging (B2A), Paris, France
Received: October 2, 2019 Accepted: March 24, 2020 Published: May 10, 2020https://doi.org/10.18632/aging.103124
How to Cite
Copyright © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Dysregulation of the circadian timing system (CTS) frequently appears during colorectal cancer (CRC) progression. In order to better understand the role of the circadian clock in CRC progression, this study evaluated in vitro how knockdown of a core circadian protein BMAL1 (BMAL1-KD) influenced the behavior of two primary human CRC cell lines (HCT116 and SW480) and a metastatic CRC cell line (SW620).
Unexpectedly, BMAL1-KD induced CRC cell-type specific responses rather than the same phenomenon throughout. First, BMAL1-KD increased AKT/mTOR activation in each CRC cell line, but to different extents. Second, BMAL1-KD-induced P53 activation varied with cell context. In a wild type P53 background, HCT116 BMAL1-KD cells quickly underwent apoptosis after shBMAL1 lentivirus transduction, while surviving cells showed less P53 but increased AKT/mTOR activation, which ultimately caused higher proliferation. In the presence of a partially functional mutant P53, SW480 BMAL1-KD cells showed moderate P53 and mTOR activation simultaneously with cell senescence. With a moderate increased AKT but unchanged mutant P53 activation, SW620 BMAL1-KD cells grew faster.
Thus, under different CRC cellular pathological contexts, BMAL1 knockdown induced relatively equal effects on AKT/mTOR activation but different effects on P53 activation, which finally triggered different CRC cell fates.