High PKCλ expression is required for ALDH1-positive cancer stem cell function and indicates a poor clinical outcome in late-stage breast cancer patients
| Autor: | Hitomi Motomura, Kazunori Sasaki, Shotaro Kanai, Yumiko Kimura, Yasunari Mano, Kazunori Akimoto, Shoma Tamori, Yohsuke Harada, Keiko Sato, Tsugumichi Sato, Yuka Ishihara, Yasushi Hara, Chotaro Onaga, Shigeo Ohno, Ayaka Ozaki, Yuka Nozaki, Hitoshi Ishiguro |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Carcinogenesis Apoptosis medicine.disease_cause Biochemistry 0302 clinical medicine Cell Movement Animal Cells Cancer Stem Cells Breast Tumors Tumor Cells Cultured Medicine and Health Sciences Small interfering RNAs Cell Cycle and Cell Division Protein Kinase C Aged 80 and over Multidisciplinary Cell Death Stem Cells Cell migration Middle Aged Prognosis Aldehyde Oxidoreductases Cancer Cell Migration Gene Expression Regulation Neoplastic Isoenzymes Survival Rate Nucleic acids Cell Motility Oncology Cell Processes 030220 oncology & carcinogenesis Neoplastic Stem Cells Medicine Female Stem cell Cellular Types Research Article Adult Programmed cell death Science Breast Neoplasms Cell Migration Biology Transfection Research and Analysis Methods 03 medical and health sciences Breast cancer Cancer stem cell Breast Cancer medicine Biomarkers Tumor Genetics Humans Non-coding RNA Molecular Biology Techniques Molecular Biology Aged Cell Proliferation Cancers and Neoplasms Biology and Life Sciences Cell Biology medicine.disease Gene regulation 030104 developmental biology Cancer cell Cancer research RNA Gene expression Follow-Up Studies Developmental Biology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 15, Iss 7, p e0235747 (2020) |
| ISSN: | 1932-6203 |
| Popis: | Despite development of markers for identification of cancer stem cells, the mechanism underlying the survival and division of cancer stem cells in breast cancer remains unclear. Here we report that PKCλ expression was enriched in basal-like breast cancer, among breast cancer subtypes, and was correlated with ALDH1A3 expression (p = 0.016, χ2-test). Late stage breast cancer patients expressing PKCλhigh and ALDH1A3high had poorer disease-specific survival than those expressing PKCλlow and ALDH1A3low (p = 0.018, log rank test for Kaplan-Meier survival curves: hazard ratio 2.58, 95% CI 1.24-5.37, p = 0.011, multivariate Cox regression analysis). Functional inhibition of PKCλ through siRNA-mediated knockdown or CRISPR-Cas9-mediated knockout in ALDH1high MDA-MB 157 and MDA-MB 468 basal-like breast cancer cells led to increases in the numbers of trypan blue-positive and active-caspase 3-positive cells, as well as suppression of tumor-sphere formation and cell migration. Furthermore, the amount of CASP3 and PARP mRNA and the level of cleaved caspase-3 protein were enhanced in PKCλ-deficient ALDH1high cells. An Apoptosis inhibitor (z-VAD-FMK) suppressed the enhancement of cell death as well as the levels of cleaved caspase-3 protein in PKCλ deficient ALDH1high cells. It also altered the asymmetric/symmetric distribution ratio of ALDH1A3 protein. In addition, PKCλ knockdown led to increases in cellular ROS levels in ALDH1high cells. These results suggest that PKCλ is essential for cancer cell survival and migration, tumorigenesis, the asymmetric distribution of ALDH1A3 protein among cancer cells, and the maintenance of low ROS levels in ALDH1-positive breast cancer stem cells. This makes it a key contributor to the poorer prognosis seen in late-stage breast cancer patients. |
| Databáze: | OpenAIRE |
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