期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 5, 页码 2341-2353出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03635-3
关键词
Chemotherapeutic agents; DHHC3; Oxidative stress; PARP inhibitor; Protein palmitoylation; Protein acyl transferases
资金
- NIH [CA42368]
- DoD [W81XWH-11-1-0112, W81XWH-11-1-0113]
The ablation of protein acyltransferase DHHC3 enhances the anti-cancer cell activities of chemotherapeutic agents by increasing oxidative stress and disabling antioxidant protections. This can lead to a greater than additive effect when combined with chemotherapeutic drugs, ultimately enhancing their anti-growth effects. Targeting DHHC3 could be a useful strategy for selectively enhancing the potency of oxidative stress-inducing anti-cancer drugs.
Ablation of protein acyltransferase DHHC3 selectively enhanced the anti-cancer cell activities of several chemotherapeutic agents, but not kinase inhibitors. To understand why this occurs, we used comparative mass spectrometry-based palmitoyl-proteomic analysis of breast and prostate cancer cell lines, +/- DHHC3 ablation, to obtain the first comprehensive lists of candidate protein substrates palmitoylated by DHHC3. Putative substrates included 22-28 antioxidant/redox-regulatory proteins, thus predicting that DHHC3 should have antioxidant functions. Consistent with this, DHHC3 ablation elevated oxidative stress. Furthermore, DHHC3 ablation, together with chemotherapeutic drug treatment, (a) elevated oxidative stress, with a greater than additive effect, and (b) enhanced the anti-growth effects of the chemotherapeutic agents. These results suggest that DHHC3 ablation enhances chemotherapeutic drug potency by disabling the antioxidant protections that contribute to drug resistance. Affirming this concept, DHHC3 ablation synergized with another anti-cancer drug, PARP inhibitor PJ-34, to decrease cell proliferation and increase oxidative stress. Hence, DHHC3 targeting can be a useful strategy for selectively enhancing potency of oxidative stress-inducing anti-cancer drugs. Also, comprehensive identification of DHHC3 substrates provides insight into other DHHC3 functions, relevant to in vivo tumor growth modulation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据