Collaborative research between Hospital 57357 and Zewail City of Science and Technology highlights the role of mitochondria in fighting breast cancer’s resistance to chemotherapy. The study titled “Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells.” was recently published in the Scientific Reports, Journal on Sept, 24, 2019
Mitochondrial aid-in-reserve may explain resistance of triple negative cancer cells to therapy
Summary: Warburg effect refers to the phenomenon observed in cancer cells where metabolic pathway is altered towards enhancement of glycolytic activity despite abundance of oxygen. This warranted the investigation of effect of glycolytic inhibitors on cancer cells, and upon testing on TNBC cells researchers recently showed that cancer cells could mitigate this inhibition by enhancing mitochondrial respiration and activation of DNA repair mechanism.
Breast cancer is the most common cancer among females, affecting more than 2 million women worldwide last year, -according to WHO reports, and also causes the greatest number of cancer-related deaths among women.
Triple-negative breast cancer (TNBC) constitutes around 20% of invasive breast cancers and is characterized by the lack of hormonal receptors. As a result, tailored therapies, such as hormonal and anti-HER2 therapies, are not applicable for the lack of target receptors.
Compared to hormone responsive cells, TNBC cells exhibit metabolic characteristics manifested by high glycolytic activity and low mitochondrial respiration. Therefore, “We wondered: What would happen if we tried to suffocate those cells by targeting their anaerobic energy production pathway? Says “Sameh Ali” head of Children’s Cancer Hospital Egypt (57357) tumor biology program and the corresponding author on the paper.
In order to answer this question, the team compared the responses of two cell lines to a common glycolytic inhibitor, the first cell line is ” MDA-MB-231 ” representative of TNBC, while the other- MCF7- is Estrogen positive and represents hormone- responsive subtypes.
“The initial results were as we expected,” he said, as about 70% of the triple-negative cells died in the first 4 hours, while the hormone-responsive cells were less affected, but the surprise emerged after leaving them for a longer time.
Revival
Iodoacetate is a potent glycolytic inhibitor, it mainly works by inhibiting (GAPDH) enzyme, a pivotal enzyme in this pathway. The pre-treatment of cancer cells with iodoacetate was reported to suppress their ability to induce tumors, hence the research team was encouraged to explore and revive the potential of iodoacetate as a simple and inexpensive drug candidate for specific targeting of breast malignancies.
While the triple-negative cells were more sensitive to the effect of iodoacetate in the first 4 hours, after 24 hours under the effect of that inhibition, most of the hormone- responsive cells died out, while TNBC cells resisted, “as if they had been revived”, Ali points out.
“We then moved to investigate the main differences between the two cell lines, on the cellular, molecular and metabolic level, with the aim of finding the underlying cause of TNBC survival, despite the death of the other cell line.” Says “Asmaa Reda”, the first author on the paper.
This investigation revealed that TNBC show lower signs of apoptotic death, lower expression of apoptotic genes, normal cell cycle regulations, but increased mRNA levels of p27 and PARP1; all consistent with enhanced cell survival.
“All these factors helped on the survival of triple-negative cells, and here comes the prominent role of mitochondria.” As most of those factors are linked to it, our results also show that the TNBC tumor cells have a more efficient mitochondria compared to their counterparts in the other cell line, which ensures that they are not deprived of a continuous source of energy, Ali said.
Based on their findings, researchers suggest that an effective treatment against TNBC can be designed by targeting mitochondria in combination with other treatments, with the aim of robbing cancer cells all their different sources of energy production.
Journal reference: Reda, A., Refaat, A., Abd-Rabou, A., Mahmoud, A., Adel, M., Sabet, S. and Ali, S. (2019). Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells. Scientific Reports, 9(1).