Posted: 20th January 2020
Researchers at St Vincent’s Institute of Medical Research (SVI) in collaboration with scientists at Flinders University in Adelaide, have uncovered a metabolic system which could lead to new strategies for therapeutic cancer treatment.
“A team at Flinders University led by Professor Janni Petersen had been investigating a metabolic system in a yeast called Schizosaccharomyces pombe, or S.pombe. She wanted to confirm that the system she had identified – which was critical for the regulation of cell growth and proliferation – was consistent within the mammalian cell system.
“What is fascinating about this yeast is that it became evolutionarily distinct about 350 million years ago, so you could argue the discovery, that we subsequently confirmed occurs in mammals, is at least as ancient as that,” said Associate Professor Jon Oakhill, Head, Metabolic Signalling Laboratory at SVI.
This project looked at two major signalling networks. Often referred to as the body’s fuel gauge; a protein called AMP-Kinase, or AMPK, regulates cellular energy, slowing cell growth down when they don’t have enough nutrients or energy to divide. The other, that of a protein complex called mTORC1/TORC1, which also regulates cell growth, increases cell proliferation when it senses high levels of nutrients such as amino acids, insulin or growth factors. A hallmark of cancer cells is their ability to over-ride these sensing systems and maintain uncontrolled proliferation.
“We have known for about 15 years that AMPK can ‘put the brakes on’ mTORC1, preventing cell proliferation” said A/Professor Jon Oakhill. “However, it was at this point that we discovered a mechanism whereby mTORC1 can reciprocally also inhibit AMPK and keep it in a suppressed state.
“In our experiments, we could see that yeast cells became highly sensitive to nutrient shortages when we disrupted the ability of mTORC1 to inhibit AMPK,” said Professor Petersen. “The cells also divided at a smaller size, indicating disruption of normal cell growth regulation.
“We measured the growth rates of cancerous mammalian cells by starving them of amino acids and energy (by depriving them of glucose) to mimic conditions found in a tumour. Surprisingly, we found that these combined stresses actually increased growth rates, which we determined was due to the cells entering a rogue ‘survival’ mode. When in this mode, they feed upon themselves so that even in the absence of appropriate nutrients the cells continue to grow. Importantly, this transition to survival mode was lost when we again removed the ability of mTORC1 to inhibit AMPK.”
“These findings provide a new opportunity for cancer treatment strategies aimed at suppressing cell proliferation in the nutrient-poor tumour microenvironment.”
The paper, entitled “TORC1 directly inhibits AMPK to promote cell proliferation under nutrient stress” has been published today in Nature Metabolism.
Other SVI researchers who participated in this study:
Dr Naomi Ling – joint first author – Metabolic Signalling Lab, Dr Ash Hoque – Metabolic Signalling Lab, Dr Kevin Ngoei – Protein Chemistry & Metabolism Unit, Dr Will Smiles – Metabolic Signalling Lab, Dr Toby Dite – Metabolic Signalling Lab (now at The University of Dundee), Dr Christopher Langendorf – Protein Chemistry & Metabolism Unit, Dr John Scott – Protein Chemistry & Metabolism Unit.
- Worldwide Cancer Research
- St. Vincent’s Institute of Medical Research
- Victorian State Government Operational Infrastructure Support Scheme
- Cancer Research UK (CRUK)
- Department of Education and Training | Australian Research Council (ARC)
- Department of Health | National Health and Medical Research Council (NHMRC)
- Flinders Foundation seeding grant