bims-lymeca 2023-02-12 papers

Int J Mol Sci. 2023 Jan 22. pii: 2176. [Epub ahead of print]24(3):

Lysosomes as a Target of Anticancer Therapy.

Wojciech Trybus, Ewa Trybus, Teodora Król.

Lysosomes are organelles containing acidic hydrolases that are responsible for lysosomal degradation and the maintenance of cellular homeostasis. They play an important role in autophagy, as well as in various cell death pathways, such as lysosomal and apoptotic death. Various agents, including drugs, can induce lysosomal membrane permeability, resulting in the translocation of acidic hydrolases into the cytoplasm, which promotes lysosomal-mediated death. This type of death may be of great importance in anti-cancer therapy, as both cancer cells with disturbed pathways leading to apoptosis and drug-resistant cells can undergo it. Important compounds that damage the lysosomal membrane include lysosomotropic compounds, antihistamines, immunosuppressants, DNA-damaging drugs, chemotherapeutics, photosensitizers and various plant compounds. An interesting approach in the treatment of cancer and the search for ways to overcome the chemoresistance of cancer cells may also be combining lysosomotropic compounds with targeted modulators of autophagy to induce cell death. These compounds may be an alternative in oncological treatment, and lysosomes may become a promising therapeutic target for many diseases, including cancer. Understanding the functional relationships between autophagy and apoptosis and the possibilities of their regulation, both in relation to normal and cancer cells, can be used to develop new and more effective anticancer therapies.

Keywords: apoptosis; autophagy; cathepsins; lysosomal membrane permeability; lysosomes

DOI: https://doi.org/10.3390/ijms24032176

Cell Death Discov. 2023 Feb 06. 9(1): 45

Gemcitabine promotes autophagy and lysosomal function through ERK- and TFEB-dependent mechanisms.

Benoît Marchand, Marc-Antoine Poulin, Christine Lawson, Lee-Hwa Tai, Steve Jean, Marie-Josée Boucher.

Gemcitabine is a first-line treatment agent for pancreatic ductal adenocarcinoma (PDAC). Contributing to its cytotoxicity, this chemotherapeutic agent is primarily a DNA replication inhibitor that also induces DNA damage. However, its therapeutic effects are limited owing to chemoresistance. Evidence in the literature points to a role for autophagy in restricting the efficacy of gemcitabine. Autophagy is a catabolic process in which intracellular components are delivered to degradative organelles lysosomes. Interfering with this process sensitizes PDAC cells to gemcitabine. It is consequently inferred that autophagy and lysosomal function need to be tightly regulated to maintain homeostasis and provide resistance to environmental stress, such as those imposed by chemotherapeutic drugs. However, the mechanism(s) through which gemcitabine promotes autophagy remains elusive, and the impact of gemcitabine on lysosomal function remains largely unexplored. Therefore, we applied complementary approaches to define the mechanisms triggered by gemcitabine that support autophagy and lysosome function. We found that gemcitabine elicited ERK-dependent autophagy in PDAC cells, but did not stimulate ERK activity or autophagy in non-tumoral human pancreatic epithelial cells. Gemcitabine also promoted transcription factor EB (TFEB)-dependent lysosomal function in PDAC cells. Indeed, treating PDAC cells with gemcitabine caused expansion of the lysosomal network, as revealed by Lysosome associated membrane protein-1 (LAMP1) and LysoTracker staining. More specific approaches have shown that gemcitabine promotes the activity of cathepsin B (CTSB), a cysteine protease playing an active role in lysosomal degradation. We showed that lysosomal function induced by gemcitabine depends on TFEB, the master regulator of autophagy and lysosomal biogenesis. Interfering with TFEB function considerably limited the clonogenic growth of PDAC cells and hindered the capacity of TFEB-depleted PDAC cells to develop orthotopic tumors.

DOI: https://doi.org/10.1038/s41420-023-01342-z

Oncogene. 2023 Feb 04.

Nutrient transporters: connecting cancer metabolism to therapeutic opportunities.

Zeribe Chike Nwosu, Mun Gu Song, Marina Pasca di Magliano, Costas A Lyssiotis, Sung Eun Kim.

Cancer cells rely on certain extracellular nutrients to sustain their metabolism and growth. Solute carrier (SLC) transporters enable cells to acquire extracellular nutrients or shuttle intracellular nutrients across organelles. However, the function of many SLC transporters in cancer is unknown. Determining the key SLC transporters promoting cancer growth could reveal important therapeutic opportunities. Here we summarize recent findings and knowledge gaps on SLC transporters in cancer. We highlight existing inhibitors for studying these transporters, clinical trials on treating cancer by blocking transporters, and compensatory transporters used by cancer cells to evade treatment. We propose targeting transporters simultaneously or in combination with targeted therapy or immunotherapy as alternative strategies for effective cancer therapy.

DOI: https://doi.org/10.1038/s41388-023-02593-x