Back to Search
Start Over
Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy
- Source :
- Cancer Biology & Therapy
- Publication Year :
- 2013
- Publisher :
- Informa UK Limited, 2013.
-
Abstract
- The present studies focused on defining the mechanisms by which anoikis-resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA. In AR cells expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. AR cells were resistant to cell killing by multiple anti-tumor cell therapies, including ERBB1/2 inhibitor + MCL-1 inhibitor treatment, and had a reduced autophagic flux response to these therapies, despite similarly exhibiting increased levels of LC3II processing. Knockdown of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells. Pre-treatment of anoikis-resistant cells with histone deacetylase inhibitors (HDACIs) for 24 h increased the levels of toxic BH3 domain proteins, reduced MCL-1 levels, and restored/re-sensitized the cell death response of AR tumor cells to multiple toxic therapies. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored the chemo-sensitivity of the tumors and prolonged animal survival. These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.
- Subjects :
- Cancer Research
Indoles
Receptor, ErbB-2
Cell
Gene Expression
Epigenesis, Genetic
necrosis
Mice
0302 clinical medicine
anoikis
Anoikis
RNA, Small Interfering
ERBB1
bcl-2-Associated X Protein
BH3 domain
0303 health sciences
biology
Brain Neoplasms
3. Good health
ErbB Receptors
Gene Expression Regulation, Neoplastic
bcl-2 Homologous Antagonist-Killer Protein
Cell killing
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Oncology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Molecular Medicine
Female
Stem cell
signaling
Bcl-2 Homologous Antagonist-Killer Protein
Research Paper
autophagy
tumor
Programmed cell death
Antineoplastic Agents, Hormonal
Cell Survival
NOXA
bcl-X Protein
Mice, Nude
Breast Neoplasms
03 medical and health sciences
Bcl-2-associated X protein
Proto-Oncogene Proteins
medicine
Animals
Humans
Pyrroles
030304 developmental biology
Pharmacology
Valproic Acid
BAK
Lapatinib
Xenograft Model Antitumor Assays
Molecular biology
Histone Deacetylase Inhibitors
Drug Resistance, Neoplasm
Quinazolines
biology.protein
Cancer research
Myeloid Cell Leukemia Sequence 1 Protein
Histone deacetylase
MCL-1
Apoptosis Regulatory Proteins
Subjects
Details
- ISSN :
- 15558576 and 15384047
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- Cancer Biology & Therapy
- Accession number :
- edsair.doi.dedup.....510c38b3cc6fa102fc9ef09fdf587a5d