Format

Send to

Choose Destination
Biochim Biophys Acta Mol Cell Res. 2019 Sep 4;1866(12):118553. doi: 10.1016/j.bbamcr.2019.118553. [Epub ahead of print]

CYP1B1 prevents proteasome-mediated XIAP degradation by inducing PKCε activation and phosphorylation of XIAP.

Author information

1
College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea.
2
College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, Seoul 06974, Republic of Korea. Electronic address: yjchun@cau.ac.kr.

Abstract

Cytochrome P450 1B1 (CYP1B1) is a key enzyme that catalyzes the metabolism of 17β-estradiol (E2) into catechol estrogens, such as 2-hydroxyestradiol (2-OHE2) and 4-hydroxyestradiol (4-OHE2). CYP1B1 is related to tumor formation and is over-expressed in a variety of cancer cells. In particular, CYP1B1 is highly expressed in hormone-related cancers such as breast cancer, ovarian cancer, or prostate cancer compared to other cancers. However, the detailed mechanisms involving this protein remain unclear. In this study, we demonstrate that CYP1B1 affects X-linked inhibitor of apoptosis protein (XIAP) expression. When CYP1B1 was over-expressed in cells, there was significant increase in the XIAP protein level, whereas the XIAP mRNA level was not affected by CYP1B1 expression. Treatment with 4-OHE2, mainly formed by CYP1B1 activity, also increased XIAP protein levels, whereas treatment with 2-OHE2 did not have a significant effect. Treatment with 4-OHE2 significantly prevented proteasome-mediated XIAP degradation. In addition, phosphorylation of XIAP on serine 87, which is known to stabilize XIAP, was up-regulated by 4-OHE2, indicating that 4-OHE2 affects XIAP stability through XIAP phosphorylation. We also found that phosphorylation of protein kinase C (PKC)ε, which is required for XIAP phosphorylation, increased when cells were treated with 4-OHE2. In summary, our data show that CYP1B1 may play an important role in preventing ubiquitin-proteasome-mediated XIAP degradation through the activation of PKCε signaling in cancer cells.

KEYWORDS:

4-OHE2; Apoptosis; CYP1B1; PKCε; Ubiquitination; XIAP

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center