Rab27B-Mediated Metabolic Reprogramming Induces Secretome Acidification and Chemoresistance in Breast Cancer Cells

Authors

  • An Hendrix Department of Medical Oncology, Ghent University Hospital, Belgium
  • Carla Ciccone Medical Genetics Branch, National Human Genome Research Institute, USA
  • Christian Gespach INSERM U673 Molecular and Clinical Oncology of Solid Tumors and INSERM U938, Université Pierre et Marie Curie-Paris, Faculté de Médecine, France
  • Marc Bracke Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Belgium
  • Olivier De Wever Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Belgium
  • Wendy Westbroek Medical Genetics Branch, National Human Genome Research Institute, USA

DOI:

https://doi.org/10.33393/jcb.2013.2035

Keywords:

Rab GTPase, Aerobic Glycolysis, Filopodia

Abstract

The secretory Rab27B small GTPase promotes invasive growth, tumourigenicity and metastasis in oestrogen receptor (ER)-positive human breast cancer cells. Coherently, increased Rab27B expression in breast cancer patients is associated with a poor prognosis. In the present study, bio-energetic profiling revealed that oxidative phosphorylation is significantly reduced in ER-positive breast cancer cells engineered to overexpress Rab27B levels as observed in invasive clinical primary breast cancer. Rab27B-induced metabolic reprogramming to aerobic glycolysis was further evidenced by increased extracellular acidification followed by cathepsin B activation and doxorubicin resistance. Transient silencing of Rab27B and stable transfection of Rab27A, and Rab27B mutants in ER-positive breast cancer cells confirmed that this response was Rab27B-specific and dependent upon Rab27B-GTP activation and vesicle membrane attachment through the C-terminal geranylgeranyl group of this small GTPase. Rab27B-driven extracellular acidification is required and is sufficient to induce filopodia-like morphological changes, primarily involved in the process of cancer cell invasion. Our data demonstrate that a Rab27B-dependent switch from oxidative phosphorylation towards aerobic glycolysis in ER-positive breast cancer cells is accompanied by acidification of the tumour environment.