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J Cell Sci. 2018 Jun 25;131(12). pii: jcs214726. doi: 10.1242/jcs.214726.

Cyclin D1 depletion interferes with oxidative balance and promotes cancer cell senescence.

Author information

1
Siriraj Center of Research for Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
2
Department of Pathology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand.
3
Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
4
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo Chuo-ku, Kumamoto 860-0811, Japan.
5
Siriraj Center of Research for Excellence (SiCORE) for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand siwanon.jir@mahidol.ac.th.

Abstract

Expression of cyclin D1 (CCND1) is required for cancer cell survival and proliferation. This is presumably due to the role of cyclin D1 in inactivation of the RB tumor suppressor. Here, we investigated the pro-survival function of cyclin D1 in a number of cancer cell lines. We found that cyclin D1 depletion facilitated cellular senescence in several cancer cell lines. Senescence triggered by cyclin D1 depletion was more extensive than that caused by the prolonged CDK4 inhibition. Intriguingly, the senescence caused by cyclin D1 depletion was independent of RB status of the cancer cell. We identified a build-up of intracellular reactive oxygen species in the cancer cells that underwent senescence upon depletion of cyclin D1 but not in those cells where CDK4 was inhibited. The higher ROS levels were responsible for the cell senescence, which was instigated by the p38-JNK-FOXO3a-p27 pathway. Therefore, expression of cyclin D1 prevents cancer cells from undergoing senescence, at least partially, by keeping the level of intracellular oxidative stress at a tolerable sub-lethal level. Depletion of cyclin D1 promotes the RB-independent pro-senescence pathway and the cancer cells then succumb to the endogenous oxidative stress levels.This article has an associated First Person interview with the first author of the paper.

KEYWORDS:

CDK4; Cyclin D1; FOXO3a; Oxidative stress; Retinoblastoma protein; Senescence

PMID:
29880532
DOI:
10.1242/jcs.214726

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