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2. ACE2 Rescues Impaired Autophagic Flux Through the PI3K/AKT Pathway After Subarachnoid Hemorrhage

Author

Enyu Pan, Peng Chen, Ke Zhou, Xin Qi, Lujun Pang, Yanjun Che, and Zhao Liu

Subjects
Subarachnoid hemorrhage, ACE2, Down-Regulation, Apoptosis, Biochemistry, Cerebral edema, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, Phosphatidylinositol 3-Kinases, Autophagy, Medicine, Animals, LY294002, cardiovascular diseases, Autophagic flux, Protein kinase B, PI3K/AKT/mTOR pathway, Neurons, Original Paper, PI3K/AKT, TUNEL assay, business.industry, General Medicine, Subarachnoid Hemorrhage, medicine.disease, nervous system diseases, chemistry, Cancer research, Angiotensin-Converting Enzyme 2, Phosphatidylinositol 3-Kinase, business, Proto-Oncogene Proteins c-akt, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract

Subarachnoid hemorrhage (SAH) is one of the life-threatening neurosurgical diseases in central nervous system. Autophagy has been previously demonstrated to exert vital roles in SAH development. Angiotensin I converting enzyme 2 (ACE2) has been revealed as a regulator of autophagy in neurosurgical diseases. However, effect of ACE2 on autophagy in SAH progression has not been clarified. First, we explored the relationship between autophagy and SAH progression by establishing a mouse model of SAH under the administration of 3-MA (the autophagy inhibitor). Next, we examined ACE2 expression in the cerebral cortex of SAH mice ex vivo with RT-qPCR. Subsequently, we assessed the biological function of ACE2 on brain injury, the autophagic flux pathway and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling ex vivo via neurological scoring, TUNEL assay, western blot analysis and immunofluorescence staining assay. Finally, we carried out rescue assays under chloroquine (CQ, the autophagic flux inhibitor) and LY294002 (the PI3K/AKT signaling inhibitor) administration. 3-MA mitigated brain injury after SAH, and ACE2 was downregulated in cerebral cortex of SAH mice. Moreover, ACE2 elevation alleviated cell apoptosis, cerebral edema, and neurological deficits, ameliorated the autophagic flux pathway and activated the PI3K/AKT signaling in SAH mice. Furthermore, CQ and LY294002 neutralized the effects of overexpressed ACE2 on neuronal apoptosis, cerebral edema, and neurological deficits in SAH mice. Overall, ACE2 lessened neuronal injury via the autophagic flux and PI3K/AKT pathways. This research might provide a potential novel direction for clinical treatment of SAH. Supplementary Information The online version contains supplementary material available at 10.1007/s11064-021-03469-w.

Published
2021

6. SARS-CoV-2 spike protein inhibits growth of prostate cancer: a potential role of the COVID-19 vaccine killing two birds with one stone

Author

Bradley D. Johnson, Ziwen Zhu, Marco Lequio, Coby G. D. Powers, Qian Bai, Huaping Xiao, Emerson Fajardo, Mark R. Wakefield, and Yujiang Fang

Subjects
Male, Cancer Research, Original Paper, Prostate cancer, CDK4, COVID-19 Vaccines, SARS-CoV-2, Cell Survival, Proliferation, Vaccination, COVID-19, Down-Regulation, Prostatic Neoplasms, Apoptosis, Hematology, General Medicine, Spike protein, Antibodies, Viral, FasL, Up-Regulation, Oncology, Cell Line, Tumor, Spike Glycoprotein, Coronavirus, Humans, Cell Proliferation
Abstract

To investigate the effects of isolated SARS-CoV-2 spike protein on prostate cancer cell survival. The effects of SARS-CoV-2 spike protein on LNCaP prostate cancer cell survival were assessed using clonogenic cell survival assay, quick cell proliferation assay, and caspase-3 activity kits. RT-PCR and immunohistochemistry were performed to investigate underlying molecular mechanisms. SARS-CoV-2 spike protein was found to inhibit prostate cancer cell proliferation as well as promote apoptosis. Further investigation revealed that anti-proliferative effects were associated with downregulation of the pro-proliferative molecule cyclin-dependent kinase 4 (CDK4). The increased rate of apoptosis was associated with the upregulation of pro-apoptotic molecule Fas ligand (FasL). SARS-CoV-2 spike protein inhibits the growth of LNCaP prostate cancer cells in vitro by a two-pronged approach of downregulating the expression of CDK4 and upregulating FasL. The introduction of SARS-CoV-2 spike protein into the body via COVID-19 vaccination may have the potential to inhibit prostate cancer in patients. This potential beneficial association between COVID-19 vaccines and prostate cancer inhibition will require more extensive studies before any conclusions can be drawn about any in vivo effects in a human model.

Published
2022

14. Enhancement by Nano-Diamino-Tetrac of Antiproliferative Action of Gefitinib on Colorectal Cancer Cells: Mediation by EGFR Sialylation and PI3K Activation

Author

Hung Yun Lin, Shwu Huey Wang, Yi Ru Chen, Chih Hsiung Wu, Liang Shun Wang, André Wendindondé Nana, Yu Chen Sh Yang, Ya Jung Shih, Tung Cheng Chang, Jacqueline Whang-Peng, Ai Shih, Yu Tang Chin, Kuan Wang, Chun A. Changou, Yu Min Liao, Steven C. Stain, and Paul J. Davis

Subjects
0301 basic medicine, Cancer Research, Colorectal cancer, Endocrinology, Diabetes and Metabolism, Mutant, Mice, Nude, Apoptosis, Drug resistance, 03 medical and health sciences, HT29 Cells, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Endocrinology, Gefitinib, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, heterocyclic compounds, skin and connective tissue diseases, neoplasms, Polyglactin 910, PI3K/AKT/mTOR pathway, Cell Proliferation, Original Paper, Endocrine and Autonomic Systems, Chemistry, Cell growth, medicine.disease, HCT116 Cells, Xenograft Model Antitumor Assays, In vitro, respiratory tract diseases, Enzyme Activation, ErbB Receptors, Thyroxine, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, Colorectal Neoplasms, medicine.drug
Abstract

Drug resistance complicates the clinical use of gefitinib. Tetraiodothyroacetic acid (tetrac) and nano-diamino-tetrac (NDAT) have been shown in vitro and in xenografts to have antiproliferative/angiogenic properties and to potentiate antiproliferative activity of other anticancer agents. In the current study, we investigated the effects of NDAT on the anticancer activities of gefitinib in human colorectal cancer cells. β-Galactoside α-2,6-sialyltransferase 1 (ST6Gal1) catalyzes EGFR sialylation that is associated with gefitinib resistance in colorectal cancers, and this was also investigated. Gefitinib inhibited cell proliferation of HT-29 cells (K-ras wild-type), and NDAT significantly enhanced the antiproliferative action of gefitinib. Gefitinib inhibited cell proliferation of HCT116 cells (K-ras mutant) only in high concentration, and this was further enhanced by NDAT. NDAT enhancedd gefitinib-induced antiproliferation in gefitinib-resistant colorectal cancer cells by inhibiting ST6Gal1 activity and PI3K activation. Furthermore, NDAT enhanced gefitinib-induced anticancer activity additively in colorectal cancer HCT116 cell xenograft-bearing nude mice. Results suggest that NDAT may have an application with gefitinib as combination colorectal cancer therapy.

Published
2018