Exosomes secreted from cardiomyocytes suppress the sensitivity of tumor ferroptosis in ischemic heart failure

by Selleckchem | Sep 05 2023

Heart failure (HF) patients in general have a higher risk of developing cancer. Several animal studies have indicated that cardiac remodeling and HF remarkably accelerate tumor progression, highlighting a cause-and-effect relationship between these two disease entities. Targeting ferroptosis, a prevailing form of non-apoptotic cell death, has been considered a promising therapeutic strategy for human cancers. Exosomes critically contribute to proximal and distant organ-organ communications and play crucial roles in regulating diseases in a paracrine manner. However, whether exosomes control the sensitivity of cancer to ferroptosis via regulating the cardiomyocyte-tumor cell crosstalk in ischemic HF has not yet been explored. Here, we demonstrate that myocardial infarction (MI) decreased the sensitivity of cancer cells to the canonical ferroptosis activator erastin or imidazole ketone erastin in a mouse model of xenograft tumor. Post-MI plasma exosomes potently blunted the sensitivity of tumor cells to ferroptosis inducers both in vitro in mouse Lewis lung carcinoma cell line LLC and osteosarcoma cell line K7M2 and in vivo with xenograft tumorigenesis model. The expression of miR-22-3p in cardiomyocytes and plasma-exosomes was significantly upregulated in the failing hearts of mice with chronic MI and of HF patients as well. Incubation of tumor cells with the exosomes isolated from post-MI mouse plasma or overexpression of miR-22-3p alone abrogated erastin-induced ferroptotic cell death in vitro. Cardiomyocyte-enriched miR-22-3p was packaged in exosomes and transferred into tumor cells. Inhibition of cardiomyocyte-specific miR-22-3p by AAV9 sponge increased the sensitivity of cancer cells to ferroptosis. ACSL4, a pro-ferroptotic gene, was experimentally established as a target of miR-22-3p in tumor cells. Taken together, our findings uncovered for the first time that MI suppresses erastin-induced ferroptosis through releasing miR-22-3p-enriched exosomes derived from cardiomyocytes. Therefore, targeting exosome-mediated cardiomyocyte/tumor pathological communication may offer a novel approach for the ferroptosis-based antitumor therapy.

Comments:

The passage you provided describes a study that explores the relationship between heart failure (HF) and cancer progression, specifically focusing on the role of exosomes and the process of ferroptosis in this interaction. Here's a breakdown of the main points:

1. Heart failure patients have a higher risk of developing cancer, suggesting a cause-and-effect relationship between these two diseases.
2. Animal studies have shown that cardiac remodeling and heart failure accelerate tumor progression.
3. Ferroptosis, a form of non-apoptotic cell death, is being investigated as a potential therapeutic strategy for cancer treatment.
4. Exosomes, small extracellular vesicles, play a crucial role in intercellular communication and can regulate diseases in a paracrine manner.
5. The study aimed to determine if exosomes influence cancer cell sensitivity to ferroptosis by regulating communication between cardiomyocytes (heart muscle cells) and tumor cells in the context of ischemic heart failure.
6. In a mouse model of xenograft tumor, it was found that myocardial infarction (MI) reduced the sensitivity of cancer cells to ferroptosis-inducing agents.
7. Exosomes derived from plasma after MI were found to significantly reduce the sensitivity of tumor cells to ferroptosis inducers both in vitro and in vivo.
8. The expression of miR-22-3p, a specific microRNA, was upregulated in failing hearts of mice with chronic MI and HF patients.
9. The researchers demonstrated that exosomes released from cardiomyocytes contained miR-22-3p and could transfer it to tumor cells.
10. Overexpression of miR-22-3p or incubation of tumor cells with post-MI exosomes decreased the ferroptotic cell death induced by erastin.
11. Inhibition of cardiomyocyte-specific miR-22-3p increased the sensitivity of cancer cells to ferroptosis, suggesting that it plays a role in suppressing ferroptosis.
12. The pro-ferroptotic gene ACSL4 was identified as a target of miR-22-3p in tumor cells.

In summary, the study suggests that myocardial infarction and heart failure release exosomes containing miR-22-3p from cardiomyocytes, which subsequently reduce the sensitivity of tumor cells to ferroptosis. This finding highlights the potential of targeting exosome-mediated communication between cardiomyocytes and tumor cells as a novel approach for antitumor therapy based on ferroptosis.