Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation

• Published in: Biochemical and biophysical research communications 2015-08, Vol.464 (3), p.862-868
• Main Authors: Ge, Xin, Lyu, Pengwei, Gu, Yuanting, Li, Lin, Li, Jingruo, Wang, Yan, Zhang, Linfeng, Fu, Chao, Cao, Zhang
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Adult; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; CARCINOGENESIS; Case-Control Studies; Cell Line, Tumor; CELL PROLIFERATION; Enzyme Activation; Female; FRUCTOSE; GLUCOSE; Glucose - metabolism; GLYCOLYSIS; Hedgehog Proteins - metabolism; HUMAN POPULATIONS; Humans; IN VITRO; Intracellular Signaling Peptides and Proteins - metabolism; LACTATES; Lactates - metabolism; MAMMARY GLANDS; Middle Aged; MODULATION; NEOPLASMS; p38 Mitogen-Activated Protein Kinases - metabolism; p38/MAPK activated kinase; PFKFB3; Phosphofructokinase-2 - metabolism; PHOSPHORYLATION; Proliferation; Protein-Serine-Threonine Kinases - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Reference Values; Serine - metabolism; SIGNALS; Smoothened Receptor; Sonic hedgehog; Transcription Factors - genetics; Transcription Factors - metabolism; Zinc Finger Protein GLI1
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2015.07.052

Sonic hesgehog (Shh) signaling has been reported to play an essential role in cancer progression. The mechanism of Shh involved in breast cancer carcinogenesis remains unclear. The present study sought to explore whether Shh signaling could regulate the glycolytic metabolism in breast cancers. Overexpression of the smoothed (Smo) and Gli-1 was found in human primary breast cancers. The expressions of Shh and Gli-1 correlated significantly with tumor size and tumor stage. In vitro, human recombinant Shh (rShh) triggered Smo and Gli-1 expression, promoted glucose utilization and lactate production, and accelerated cell proliferation in MCF-7 and MDA-MB-231 cells. Notably, rShh did not alter 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) expression but augmented PFKFB3 phosphorylation on ser461, along with elevated fructose-2,6-bisphosphate (F2,6BP) generation by MCF-7 and MDA-MB-231 cells. This effect could be dampened by Smo siRNA but not by Gli-1 siRNA. In addition, our data showed the upregulated expressions of MAPK by rShh and elevatory PFKFB3 phosphorylation by p38/MAPK activated kinase (MK2). In conclusion, our study characterized a novel role of Shh in promoting glycolysis and proliferation of breast cancer cells via PFKFB3 phosphorylation, which was mediated by Smo and p38/MK2. •Overexpression of Smo and Gli-1 was found in human primary breast cancers.•Shh promoted glucose utilization, lactate production, and cell proliferation.•Shh did not alter PFKFB3 expression but augmented PFKFB3 phosphorylation on ser461.•Shh acts on PFKFB3 phosphorylation via Smo and p38 MAPK/MK2.