A gene that codes for a mitochondrial protein has been identified as a potential therapeutic target for prostate cancers that have spread to other parts of the body and evade current treatment strategies.
Mitochondria are bioenergetic, biosynthetic, and signalling organelles that have been implicated in the formation of cancer and also in therapy resistance. Researchers from the University of Colorado Cancer Centre discovered that prostate tumour cell use mitochondria to control their growth and detect stress that can destroy the tumour cell. Furthermore, they found that MIRO2, which is located in the nuclear genome but encodes a mitochondrial outer membrane protein, is raised in patients with recurring or metastatic prostate cancer and that higher expression of the gene was linked to low survival rates in patients.
'We know that tumour cells are very resistant to stress in general; that's what makes them so hard to target with therapies,' said Dr Cecilia Caino, corresponding author on this study published in Molecular Cancer Research. 'But when the tumours grow too fast, they start running out of nutrients to keep building. They utilize this mitochondrial pathway that we describe to slow down for a moment, adapt, and expand their capacity to synthesise more blocks to build the cells.'
In this study, the scientists used CRISPR/Cas9 genome editing to knock out the MIRO2 gene in different cancer cell lines and subsequently deplete the protein. In doing so, they discovered reduced cancer cell growth in the majority of cancer cell lines tested, and in all prostate cancer cell lines tested. This result was also confirmed in vivo, in mice, where depletion of MIRO2 reduced tumour growth and lowered cancer cell proliferation.
This research further discovered that another gene, GCN1, was also overexpressed in prostate cancer and thus implicated in controlling cancer cell biology. MIRO2 binds with GCN1 to form a protein compound and the MIRO2-GCN1 interaction is also increased in prostate cancer.
Hormone therapy is currently used to treat many prostate cancers; however, patients can develop a resistance to these drugs over time, resulting in the cancer becoming more aggressive. The scientists believe that targeting the MIRO2-GCN1 protein compound will inhibit the mitochondrial process that prevents tumour cells from destroying themselves.
Dr Caino concluded: 'Our data suggests that targeting the MIRO2-GCN1 axis may selectively affect tumours while minimising side effects on normal tissues.'
Future research will assess if this line of treatment is effective in animal models that have metastases to determine whether the treatment can eliminate the tumour or even prevent metastasis from occurring.