Biology subjects

Karshafian, R.

Publications and source records attributed to Karshafian, R..

4 recordsLinked to original sources

bioRxiv2026

Mitophagy is required for cell survival upon ultrasound and microbubble therapeutic exposure

Ultrasound-stimulated microbubble (USMB) sonoporation treatment is an emerging strategy for cancer therapy that enhances drug delivery by perforating the plasma membrane. This membrane permeabilization also causes cellular metabolic stress as cells leak metabolites such as ATP and amino acids. Collectively, cells may die in response to excess membrane damage and stress. However, many cells survive the USMB insult by engaging membrane repair and adaptation pathways such as stimulation of AMPK. In this study, we investigated the impact of USMB treatment on mitochondria and their role in post-exposure cellular survival. We found that USMB causes mitochondrial fragmentation and decreases mitochondrial membrane potential. Subsequently, autophagy and Parkin-dependent mitophagy are triggered post-USMB treatment in an AMPK-dependent mechanism. Importantly, Parkin silencing and PINK1 inhibition augment cell death when combined with USMB exposure, suggesting that mitophagy is an important cell survival process in response to USMB. We propose that combining USMB with inhibitors of mitophagy and metabolic stress adaptation is a strong candidate for therapeutic development to treat solid tumours.

cell biology↗

bioRxiv2022

AMP-activated protein kinase (AMPK) is required for recovery from metabolic stress induced by ultrasound microbubble treatment

Ultrasound and microbubbles (USMB) is a promising strategy for cancer therapy. USMB can induce a variety of effects on cells including transient formation of plasma membrane pores (sonoporation) and enhanced endocytosis, which enhance drug delivery, and can also lead to enhanced cell death. However, the outcomes of USMB on cell physiology are heterogeneous, in that USMB elicits cell death in a proportion of cells while exerting minimal effects on others. This suggests that mechanisms of adaptation following USMB allow some cells to survive and/or proliferate. The molecular mechanisms of adaptation to USMB-induced stress remain poorly understood, thus potentially hindering broad therapeutic applications of USMB. Herein, we used several triple negative breast cancer cells to study the effect of USMB-induced metabolite stress and the role of AMPK as a response to this stress. We found that USMB alters steady-state levels of amino acids, glycolytic intermediates, and citric acid cycle intermediates. USMB treatment acutely reduces ATP levels and stimulates AMP-activated protein kinase (AMPK) phosphorylation and activation. Further, AMPK is required to restore ATP levels in cells that survived the initial insult and support cell proliferation post-USMB treatment. These results suggest that AMPK and metabolic perturbations are likely determinants of the anti-neoplastic efficacy of USMB treatment.

cell biology↗

bioRxiv2021

Multiscale interactome analysis coupled with off-target drug predictions reveals drug repurposing candidates for human coronavirus disease

The COVID-19 pandemic has led to an urgent need for the identification of new antiviral drug therapies that can be rapidly deployed to treat patients with this disease. COVID-19 is caused by infection with the human coronavirus SARS-CoV-2. We developed a computational approach to identify new antiviral drug targets and repurpose clinically-relevant drug compounds for the treatment of COVID-19. Our approach is based on graph convolutional networks (GCN) and involves multiscale host-virus interactome analysis coupled to off-target drug predictions. Cellbased experimental assessment reveals several clinically-relevant repurposing drug candidates predicted by the in silico analyses to have antiviral activity against human coronavirus infection. In particular, we identify the MET inhibitor capmatinib as having potent and broad antiviral activity against several coronaviruses in a MET-independent manner, as well as novel roles for host cell proteins such as IRAK1/4 in supporting human coronavirus infection, which can inform further drug discovery studies.

cell biology↗

bioRxiv2019

Targeted enhancement of flotillin-dependent endocytosis augments cellular uptake and impact of cytotoxic drugs

Cellular uptake is limiting for the efficacy of many cytotoxic drugs used to treat cancer. Identifying endocytic mechanisms that can be modulated with targeted, clinically-relevant interventions is important to enhance the efficacy of various cancer drugs. We identify that flotillin-dependent endocytosis can be targeted and upregulated by ultrasound and microbubble (USMB) treatments to enhance uptake and efficacy of cancer drugs such as cisplatin. USMB involves targeted ultrasound following administration of encapsulated microbubbles, used clinically for enhanced ultrasound image contrast. USMB treatments robustly enhanced internalization of the molecular scaffold protein flotillin, as well as flotillin-dependent fluid-phase internalization, a phenomenon dependent on the protein palmitoyltransferase DHHC5 and the Src-family kinase Fyn. USMB treatment enhanced DNA damage and cell killing elicited by the cytotoxic agent cisplatin in a flotillin-dependent manner. Thus, flotillin-dependent endocytosis can be modulated by clinically-relevant USMB treatments to enhance drug uptake and efficacy, revealing an important new strategy for targeted drug delivery for cancer treatment.

cell biology↗