Galectin-3 Up-Regulation in Hypoxic and Nutrient Deprived Microenvironments Promotes Cell Survival

Author(s)

Ikemori, Rafael Yamashita ^[1] ; Longo Machado, Camila Maria ^{[1, 2]} ; Furuzawa, Karina Mie ^[1] ; Nonogaki, Suely ^[3] ; Osinaga, Eduardo ^[4] ; Umezawa, Kazuo ^[5] ; de Carvalho, Marcelo Alex ^[6] ; Verinaud, Liana ^[7] ; Chammas, Roger ^[1]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo - Brazil

^[2] Lab Invest Med Med Nucl LIM43, Sao Paulo - Brazil

^[3] Adolfo Lutz Inst, Dept Patol, Sao Paulo - Brazil

^[4] La Univ La Republ, Fac Med, Montevideo - Uruguay

^[5] Aichi Med Univ, Nagakute, Aichi 48011 - Japan

^[6] Inst Fed Rio de Janeiro, Inst Nacl Canc, Rio De Janeiro, RJ - Brazil

^[7] Univ Estadual Campinas, Inst Biol, Dept Microbiol & Immunol, Campinas, SP - Brazil

• Document type: Journal article
• Source: PLoS One; v. 9, n. 11 NOV 4 2014.
• Web of Science Citations: 21

Abstract

Galectin-3 (gal-3) is a beta-galactoside binding protein related to many tumoral aspects, e. g. angiogenesis, cell growth and motility and resistance to cell death. Evidence has shown its upregulation upon hypoxia, a common feature in solid tumors such as glioblastoma multiformes (GBM). This tumor presents a unique feature described as pseudopalisading cells, which accumulate large amounts of gal-3. Tumor cells far from hypoxic/nutrient deprived areas express little, if any gal-3. Here, we have shown that the hybrid glioma cell line, NG97ht, recapitulates GBM growth forming gal-3 positive pseudopalisades even when cells are grafted subcutaneously in nude mice. In vitro experiments were performed exposing these cells to conditions mimicking tumor areas that display oxygen and nutrient deprivation. Results indicated that gal-3 transcription under hypoxic conditions requires previous protein synthesis and is triggered in a HIF-1 alpha and NF-kappa B dependent manner. In addition, a significant proportion of cells die only when exposed simultaneously to hypoxia and nutrient deprivation and demonstrate ROS induction. Inhibition of gal-3 expression using siRNA led to protein knockdown followed by a 1.7-2.2 fold increase in cell death. Similar results were also found in a human GBM cell line, T98G. In vivo, U87MG gal-3 knockdown cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and increased time for tumor engraftment. These results indicate that gal-3 protected cells from cell death under hypoxia and nutrient deprivation in vitro and that gal-3 is a key factor in tumor growth and engraftment in hypoxic and nutrient-deprived microenvironments. Overexpression of gal-3, thus, is part of an adaptive program leading to tumor cell survival under these stressing conditions. (AU)

• FAPESP's process: 09/10857-0 - Evaluation of the mechanism of anti-apoptotic effect of galectin-3 in glioma cells and its role in the development of pseudopalisades in vivo
• Grantee: Rafael Yamashita Ikemori
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 98/14247-6 - Center for Research on Cell-Based Therapy
• Grantee: Marco Antonio Zago
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC