MSc.Thesis Defense:Cemile Uslu

TARGETING MITOCHONDRIA WITH ANTIBIOTICS AS A MEANS OF OVERCOMING CHEMORESISTANCE IN TRIPLE NEGATIVE BREAST CANCER

Cemile Uslu
Molecular Biology, Genetics and Bioengineering, MSc. Thesis, 2024

Thesis Jury

Asst. Prof. Alex Lyakhovich (Thesis Advisor)

Asst. Prof. Nur Mustafaoğlu

Asst. Prof. Şükrü Anıl Doğan

Date & Time: 23.07.2024 – 15.00

Place: FENS L027

Keywords : TNBC, metastasis, chemoresistance, OXPHOS, antibiotics

Zoom Link: https://sabanciuniv.zoom.us/j/97069604751

Abstract

Cancer has remained a factor of mortality worldwide for more than half a century. Among many others, breast cancer is the most important cause of death in women. A particular subtype known as triple negative breast cancer (TNBC) is the most aggressive and has the worst clinical prognosis. The absence of estrogen receptors (ER), progesterone receptors (PR) and low expression of human epidermal growth factor receptors (HER2) allows TNBC to avoid hormonal therapy, forcing the search for other anti-cancer therapy approaches. Since cancer patients do not die directly from primary malignant tumors, but from metastasis, which is often accompanied by cancer resistance, efforts need to be directed specifically at combating the emergence of metastatic disease. In part, the development of metastases is promoted by so-called cancer stem cells (CSCs) and - a subset of cells living in the tumor with a specific microenvironment, which eventually allows such cells to develop progenitors and colonize in distal organs giving metastases. CSCs are slow dividing and therefore resistant to chemotherapy cells, which often leads to tumor recurrence. In addition, a regular course of chemo- or radiotherapy can select a specific population of cancer resistant cells (CRC) that contribute as much to chemoresistance as CSCs. As shown by various studies, drug-resistant cancer cells exhibit higher levels of mitochondrial respiration than sensitive cancer cells, which is often fueled by ATP from mitochondria-driven oxidative phosphorylation (OXPHOS). Recently, it was suggested that OXPHOS inhibitors may resensitize chemoresistant cells to anticancer therapy. Taking into account the endosymbiotic origin of mitochondria from alphaproteobacteria, we attempted to select antibiotics as chemotherapeutic agents that could inhibit OXPHOS in chemoresistant cells. As a model, we used to cisplatin- resistant TNBC cells. Such cells were found to be OXPHOS-dependent an showed higher oxygen consumption rate, higher doubling time, overexpression of stemness markers and higher metastatic potential compared to sensitive counterparts. After analyzing more than 50 antibiotics, two promising drugs (Amoxicillin and Fosmidomycin soidum salt) with higher toxic effects on chemoresistant cancer cells were selected. Those drugs showed suppression of OXPHOS, decrease in metastatic potential and increase in the autophagy in resistant cells. Overall, our results suggest that some bactericidal antibiotics with proven activity against mitochondria may provide an alternative approach to treat patients with chemoresistant tumors.