Myoferlin protects colon cancer cells from cell death
Olivier Peulen's group at the Metastasis Research Laboratory (MRL, V. Castronovo and A. Bellahcène, GIGA-Cancer) shows that myoferlin protects colon cancer cells from a p53-induced cell death. Multimodal chemotherapy, targeting myoferlin and restoring p53 activity, could be considered as relevant in patients with this cancer.
Colon cancer is the third most-diagnosed form of cancer, whose incidence and mortality continues to increase among the youngest. Although considerable progress has been made in the diagnosis and treatment of this disease, the latest epidemiological studies reveal that 10% of new cancer cases are colon cancer. In consequence, it remains crucial to find new strategies and therapeutic targets to develop an effective treatment against this disease.
For almost 10 years, the MRL has been working on the identification of biomarkers involved in different cancers. In this context, myoferlin has been detected as overexpressed in patients with pancreatic cancer or breast cancer. This protein, which is involved in the biology of the plasma membrane, has a tumor promotion function that is still incompletely elucidated. The work of the MRL demonstrated a link between myoferlin and the metabolic reprogramming of cancer cells in pancreas or breast. The importance of this protein in colon cancer has never been mentioned. It's now done.
Gilles Rademaker, working under the supervision of Olivier Peulen, observed an association between the abundance of myoferlin in human colon tumors and the poor survival of patients. Patients who express high myoferlin level would be 2.6 times more likely to die than patients who express low myoferlin level. They found that, like pancreatic tumors, myoferlin was able to maintain high mitochondrial activity and an optimal mitochondrial network in colon cancer cells. They also demonstrated that the elimination of myoferlin from colon cancer cells reduced mitochondrial activity and was followed by an accumulation of reactive oxygen species and a reduction in cancer cell survival. This effect is associated with an accumulation of DNA damage in cancer cells and with cell death caused by the p53 protein, considered as the genome guardian. Unfortunately, 50% of colon tumors no longer possess the active p53 protein and therefore resist to the myoferlin elimination. Fortunately, the researchers showed that reactivation of the p53 protein with a compound called PRIMA-1 resensitized cancer cells to the elimination of myoferlin.
These results open interesting therapeutic perspectives because 75% of colon tumors express abundantly myoferlin. By suppressing myoferlin with currently developing pharmacological compounds, it would be possible to induce DNA damage that is fatal to the tumor cell. In addition, the suppression of myoferlin would limit the activity of the mitochondria, essential to the formation of metastases. Olivier Peulen’s team is currently studying this aspect.
Source
Oncogenesis (2019) 8:21. https://doi.org/10.1038/s41389-019-0130-6. Human côlon cancer cells highly express myoferlin to maintain a fit mitochondrial network and escape p53-driven apoptosis. Gilles Rademaker, Brunella Costanza, Justine Bellier, Michael Herfs, Raphaël Peiffer, Ferman Agirman, Naïma Maloujahmoum, Yvette Habraken, Philippe Delvenne, Akeila Bellahcène, Vincent Castronovo, Olivier Peulen
A. Myoferlin staining (brown) in colon tumour and normal adjacent tissue. B. DNA damage (red) in colon cancer cells (SW480) after myoferlin deletion. C. Mitochondrial network (orange) in colon cancer cell expressing myoferlin.
