Allopregnanolone suppresses glioblastoma survival through decreasing DPYSL3 and S100A11 expression

Yin-Hsun Feng; Sher-Wei Lim; Hong-Yi Lin; Shao-An Wang; Sung-Po Hsu; Tzu-Jen Kao; Chiung-Yuan Ko; Tsung-I Hsu

doi:10.1016/j.jsbmb.2022.106067

Allopregnanolone suppresses glioblastoma survival through decreasing DPYSL3 and S100A11 expression

J Steroid Biochem Mol Biol. 2022 May:219:106067. doi: 10.1016/j.jsbmb.2022.106067. Epub 2022 Jan 31.

Authors

Yin-Hsun Feng¹, Sher-Wei Lim², Hong-Yi Lin³, Shao-An Wang⁴, Sung-Po Hsu⁵, Tzu-Jen Kao⁶, Chiung-Yuan Ko⁷, Tsung-I Hsu⁸

Affiliations

¹ Chi Mei Medical Center, Tainan 71004, Taiwan.
² Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan; Department of Neurosurgery, Chi-Mei Medical Center, Tainan 722, Taiwan; Department of Nursing, Min-Hwei College of Health Care Management, Tainan 736, Taiwan.
³ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan.
⁴ School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
⁵ Department of Physiology, School of Medicine, Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
⁶ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei 110, Taiwan.
⁷ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei 110, Taiwan. Electronic address: ko680108@tmu.edu.tw.
⁸ Graduate Institute of Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; The Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; International Master Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei 110, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei 110, Taiwan. Electronic address: dabiemhsu@tmu.edu.tw.

PMID: 35114375
DOI: 10.1016/j.jsbmb.2022.106067

Abstract

Allopregnanolone (allo) is a physiological regulator of neuronal activity that treats multiple neurological disorders. Allo penetrates the blood-brain barrier with very high efficiency, implying that allo can treat CNS-related diseases, including glioblastoma (GBM), which always recurs after standard therapy. Hence, this study aimed to determine whether allo has a therapeutic effect on GBM. We found that allo enhanced temozolomide (TMZ)-suppressed cell survival and proliferation of TMZ-resistant cells. In particular, allo enhanced TMZ-inhibited cell migration and TMZ-induced apoptosis. Additionally, allo strongly induced DNA damage characterized by γH2Ax. Furthermore, quantitative proteomic analysis, iTRAQ, showed that allo significantly decreased the levels of DPYSL3, S100A11, and S100A4, reflecting the poor prognosis of patients with GBM confirmed by differential gene expression and survival analysis. Moreover, single-cell RNA-Seq revealed that S100A11, expressed in malignant cells, oligodendrocytes, and macrophages, was significantly associated with immune cell infiltration. Furthermore, overexpression of DPYSL3 or S100A11 prevented allo-induced cell death. In conclusion, allo suppresses GBM cell survival by decreasing DPYSL3/S100A11 expression and inducing DNA damage.

Keywords: Allopregnanolone; Glioblastoma; iTRAQ.

MeSH terms

Antineoplastic Agents, Alkylating
Apoptosis / drug effects
Brain Neoplasms* / drug therapy
Brain Neoplasms* / metabolism
Brain Neoplasms* / pathology
Cell Line, Tumor
Drug Resistance, Neoplasm
Glioblastoma* / drug therapy
Glioblastoma* / metabolism
Glioblastoma* / pathology
Humans
Muscle Proteins* / antagonists & inhibitors
Muscle Proteins* / biosynthesis
Neoplasm Recurrence, Local
Pregnanolone* / pharmacology
Proteomics
S100 Proteins* / antagonists & inhibitors
S100 Proteins* / biosynthesis
Temozolomide / pharmacology

Substances

Antineoplastic Agents, Alkylating
DPYSL3 protein, human
Muscle Proteins
S100 Proteins
S100A11 protein, human
Pregnanolone
Temozolomide