In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1254-1254
Abstract:
As a consequence of increased glucose metabolism and poor perfusion, solid tumors are acidic. Tumor cells must overcome this physical microenvironmental barrier in order to progress. To better understand phenotypes associated with extracellular acidosis, MDA-MB-231 human breast carcinoma cells were acutely and chronically exposed to low pH (6.7) growth conditions. In the acute phase, low pH reduced proliferation, induced a G1cell cycle arrest, and increased cytoplasmic vacuolization, with no observable effect on cell viability. Following chronic (3 month) exposure, MDA-MB-231 cells had restored proliferation to control levels with no cell cycle arrest, yet remained highly vacuolated. Our prior work identified a subset of these vacuoles to be autophagic, while the rest appeared to be lipid droplets. Confocal microscopy of MDA-MB 231 cells stained with Nile Red, an intracellular fluorescent lipophilic dye, identified the cytoplasmic vacuoles as lipid aggregates. A significant number of lipid aggregates accumulated in low pH treated MDA-MB-231 cells (p & lt; 0.01), and this was also observed in a series of breast and non-breast cancer cell lines, suggesting that this is a universal response to extracellular acidosis. To investigate the source of the lipid, it has been observed that accumulation is serum dependent; indicating that it is either dependent on growth factors or comes from an exogenous (albumin) source. To investigate a de novo mechanism, high resolution NMR spectroscopy was used to measure 13C enriched lactate isotopomers following metabolism of D-[1,2-13C] glucose. These analyses showed that glucose flux through the pentose phosphate pathway was three-fold higher in low pH cells, compared to controls, representing a major shift in glucose metabolism from Embden Meyerhoff to the Pentose Phosphate pathway, which results in increased production of NADPH, necessary for de novo lipid synthesis. Autofluorescence microscopy showed an altered distribution of NAD(P)H under acidic conditions. Furthermore, C75, a fatty acid synthase inhibitor, induced significant cytotoxicity in low pH treated MDA-MB-231 cells, but not controls. This is further indicative of a de novo mechanism. These data suggest that the cellular survival response to extracellular acidosis depends on lipid accumulation and profound changes in glucose metabolism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1254. doi:10.1158/1538-7445.AM2011-1254
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-1254
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
