title: Sonic hedgehog stimulates glycolysis and proliferation of breast cancer cells: Modulation of PFKFB3 activation.
abstract: 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 ser(461), 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.
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Ge
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Pengwei
authors.initials: P
authors.lastname: Lyu
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Yuanting
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Jingruo
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Linfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Ultrasonography, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Fu
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China. Electronic address: zzzhangcao@126.com.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Cao
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008875:Middle Aged; D025481:Phosphofructokinase-2 / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D012016:Reference Values; D012694:Serine / Q000378:metabolism; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D005947:Glucose; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007773:Lactates; D025481:Phosphofructokinase-2; D017346:Protein Serine-Threonine Kinases; D043562:Receptors, G-Protein-Coupled; D012694:Serine; D000072086:Smoothened Receptor; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C400551:GLI1 protein, human; C509239:SHH protein, human; C491023:SMO protein, human; C107345:PFKFB3 protein, human
keywords: Breast cancer; Glycolysis; PFKFB3; Proliferation; Sonic hedgehog; p38/MAPK activated kinase