| Full text | |
| Author(s): |
Moretti, Isabele Fattori
;
Lerario, Antonio Marcondes
;
Sola, Paula Rodrigues
;
Macedo-da-Silva, Janaina
;
Baptista, Mauricio da Silva
;
Palmisano, Giuseppe
;
Oba-Shinjo, Sueli Mieko
;
Marie, Suely Kazue Nagahashi
Total Authors: 8
|
| Document type: | Journal article |
| Source: | CANCERS; v. 15, n. 3, p. 18-pg., 2023-02-01. |
| Abstract | |
Simple Summary An analysis of metformin (MET) treatment in combination with temozolomide (TMZ) in two glioblastoma cell lines, U87MG and A172, stimulated with lipopolysaccharide (LPS), a TLR4 agonist was conducted. Both cells presented blunted mitochondrial respiration leading to oxidative stress after MET treatment, and decreased cell viability after MET + TMZ treatment. U87MG cells presented increased apoptosis after MET + LPS + TMZ treatment by increment of ER stress, and downregulation of BLC2. A172, with an upregulated antioxidant background, including SOD1, exhibited cell cycle arrest after MET + TMZ treatment. The observed differential response was associated with a distinct metabolic status: glycolytic/plurimetabolic (GPM) subtype in U87MG and mitochondrial (MTC) in A172. TCGA-GBM-RNASeq in silico analysis showed that GPM-GBM cases with an activated TLR4 pathway might respond to MET, but the concomitant CXCL8/IL8 upregulation may demand a combination treatment with an IL8 inhibitor. MET combined with an antioxidant inhibitor, such as anti-SOD1, may be indicated for MTC-GBM cases. Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET + TMZ and MET + LPS + TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET + LPS + TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of SOD2 and genes related to the TLR4 signaling pathway, including IL1B and CXCL8. A172 cells attained upregulated antioxidant gene expression, particularly SOD1, TXN and PRDX1-5, while MET treatment led to cell-cycle arrest. In silico analysis of the TCGA-GBM-RNASeq dataset indicated that the glycolytic plurimetabolic (GPM)-GBM subtype had a transcriptomic profile which overlapped with U87MG cells, suggesting GBM cases exhibiting this metabolic background with an activated inflammatory TLR4 pathway may respond to MET treatment. For cases with upregulated CXCL8, coding for IL8 (a pro-angiogenic factor), combination treatment with an IL8 inhibitor may improve tumor growth control. The A172 cell line corresponded to the mitochondrial (MTC)-GBM subtype, where MET plus an antioxidant inhibitor, such as anti-SOD1, may be indicated as a combinatory therapy. (AU) | |
| FAPESP's process: | 20/04923-0 - SARS-CoV-2 glycosylation: a blueprint structural insight for understanding COVID-19 pathogenesis |
| Grantee: | Giuseppe Palmisano |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 18/18257-1 - Multi-user equipment approved in grant 14/06863-3: HPLC system configured for analysis of carbohydrates, amino acidis, peptides and glycoproteins |
| Grantee: | Giuseppe Palmisano |
| Support Opportunities: | Multi-user Equipment Program |
| FAPESP's process: | 04/12133-6 - Search for molecular markers related to the diagnosis and prognosis of tumors of the central nervous system |
| Grantee: | Suely Kazue Nagahashi Marie |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 20/02988-7 - Decoding the impact of microenvironment and signaling pathways in health and disease in brain, adrenal gland and kidney |
| Grantee: | Suely Kazue Nagahashi Marie |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 21/00140-3 - Understanding the role of protein arginylation in health and disease through analytical and biological approaches |
| Grantee: | Janaína Macedo da Silva |
| Support Opportunities: | Scholarships in Brazil - Doctorate |
| FAPESP's process: | 13/07937-8 - Redoxome - Redox Processes in Biomedicine |
| Grantee: | Ohara Augusto |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |