Autophagy modulation effect on homotypic transfer of intracellular components via tunneling nanotubes in mesenchymal stem cells.

BACKGROUND: Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation. METHODS: MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography. RESULT: Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator. CONCLUSIONS: In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies.

The future of cancer therapy: exploring the potential of patient-derived organoids in drug development.

Cancer therapy is on the brink of a significant transformation with the inclusion of patient-derived organoids (PDOs) in drug development. These three-dimensional cell cultures, directly derived from a patient's tumor, accurately replicate the complex structure and genetic makeup of the original cancer. This makes them a promising tool for advancing oncology. In this review, we explore the practical applications of PDOs in clinical drug screening and pharmacognostic assessment, as well as their role in refining therapeutic strategies. We provide insights into the latest advancements in PDO technology and its implications for predicting treatment responses and facilitating novel drug discoveries. Additionally, we address the operational challenges associated with incorporating PDOs into the drug development process, such as scaling up organoid cultures, ensuring consistent results, and addressing the ethical use of patient-derived materials. Aimed at researchers, clinicians, and key stakeholders in oncology, this article aims to succinctly present both the extraordinary potential and the obstacles to integrating PDOs, thereby shedding light on their prospective impact on the future of cancer treatment.

A selective androgen receptor modulator, S4, displays robust anti-cancer activity on hepatocellular cancer cells by negatively regulating PI3K/AKT/mTOR signalling pathway.

Hepatocellular carcinoma (HCC) is a major global health problem that often correlates with poor prognosis. Due to the insufficient therapy options with limited benefits, it is crucial to identify new therapeutic approaches to overcome HCC. One of the vital signaling pathways in organ homeostasis and male sexual development is Androgen Receptor (AR) signaling. Its activity affects several genes that contribute to cancer characteristics and have essential roles in cell cycle progression, proliferation, angiogenesis, and metastasis. AR signaling has been shown to be misregulated in many cancers, including HCC, suggesting that it might contribute to hepatocarcinogenesis. Targeting AR signaling using anti-androgens, AR inhibitors, or AR-degrading molecules is a powerful and promising strategy to defeat HCC. In this study, AR signaling was targeted by a novel Selective Androgen Receptor Modulator (SARM), S4, in HCC cells to evaluate its potential anti-cancer effect. To date, S4 activity in cancer has not been demonstrated, and our data unrevealed that S4 significantly impaired HCC growth, migration, proliferation, and induced apoptosis through inhibiting PI3K/AKT/mTOR signaling. Since PI3K/AKT/mTOR signaling is frequently activated in HCC and contributes to its aggressiveness and poor prognosis, its negative regulation by the downregulation of critical components via S4 was a prominent finding. Further studies are necessary to investigate the S4 action mechanism and anti-tumorigenic capacity in in-vivo.