Abstract：
BACKGROUND:Cytosolic deacetylase histone deacetylase 6 (HDAC6) is involved in the autophagy degradation pathway of malformed proteins, an important survival mechanism in cancer cells. We evaluated modulation of autophagy-related proteins and cell death by the HDAC6-selective inhibitor C1A. METHODS:Autophagy substrates (light chain-3 (LC-3) and p62 proteins) and endoplasmic reticulum (ER) stress phenotype were determined. Caspase-3/7 activation and cellular proliferation assays were used to assess consequences of autophagy modulation. RESULTS:C1A potently resolved autophagy substrates induced by 3-methyladenine and chloroquine. The mechanism of autophagy inhibition by HDAC6 genetic knockout or C1A treatment was consistent with abrogation of autophagosome-lysosome fusion, and decrease of Myc protein. C1A alone or combined with the proteasome inhibitor, bortezomib, enhanced cell death in malignant cells, demonstrating the complementary roles of the proteasome and autophagy pathways for clearing malformed proteins. Myc-positive neuroblastoma, KRAS-positive colorectal cancer and multiple myeloma cells showed marked cell growth inhibition in response to HDAC6 inhibitors. Finally, growth of neuroblastoma xenografts was arrested in vivo by single agent C1A, while combination with bortezomib slowed the growth of colorectal cancer xenografts. CONCLUSIONS:C1A resolves autophagy substrates in malignant cells and induces cell death, warranting its use for in vivo pre-clinical autophagy research.
journal_name
Br J Cancerjournal_title
British journal of cancerauthors
Kaliszczak M,van Hechanova E,Li Y,Alsadah H,Parzych K,Auner HW,Aboagye EOdoi
10.1038/s41416-018-0232-5subject
Has Abstractpub_date
2018-11-01 00:00:00pages
1278-1287issue
10eissn
0007-0920issn
1532-1827pii
10.1038/s41416-018-0232-5journal_volume
119pub_type
杂志文章abstract：:In a prospective cohort study in Denmark of 8736 randomly selected people, no evidence was found among 1011 subjects who developed cancer that self-reported stressful major life events had increased their risk for cancer. ...
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pub_type： 临床试验,杂志文章
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pub_type： 杂志文章,随机对照试验
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pub_type： 杂志文章
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pub_type： 杂志文章
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更新日期：2016-06-28 00:00:00
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