BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways

May 11, 2020Aging

Reducing BMAL1 changes colon cancer cell survival by shifting the balance between growth and cell death pathways

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

BMAL1 knockdown resulted in increased AKT/mTOR activation across all examined colorectal cancer cell lines.

Different colorectal cancer cell lines responded uniquely to BMAL1 knockdown.
HCT116 cells underwent apoptosis with reduced P53 activation and increased AKT/mTOR activation, leading to higher proliferation.
SW480 cells exhibited moderate P53 and mTOR activation, resulting in cell senescence.
SW620 cells showed faster growth with increased AKT activation but unchanged mutant P53 activation.
BMAL1 knockdown affected P53 activation differently depending on the cellular context, influencing colorectal cancer cell fates.

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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 evaluatedhow 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. in vitro

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BMAL1 knockdown triggers different colon carcinoma cell fates by altering the delicate equilibrium between AKT/mTOR and P53/P21 pathways

Abstract

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