Exploring MicroRNA and Exosome Involvement in Malignant Pleural Mesothelioma Drug Response

by Selleckchem | Jun 20 2023

Malignant pleural mesothelioma (MPM) is a deadly thoracic malignancy and existing treatment options are limited. Chemotherapy remains the most widely used first-line treatment regimen for patients with unresectable MPM, but is hampered by drug resistance issues. The current study demonstrated a modest enhancement of MPM cell sensitivity to chemotherapy drug treatment following microRNA (miRNA) transfection in MPM cell lines, albeit not for all tested miRNAs. This effect was more pronounced for FAK (PND-1186) small molecule inhibitor treatment; consistent with previously published data. We previously established that MPM response to survivin (YM155) small molecule inhibitor treatment is unrelated to basal survivin expression. Here, we showed that MPM response to YM155 treatment is enhanced following miRNA transfection of YM155-resistant MPM cells. We determined that YM155-resistant MPM cells secrete a higher level of exosomes in comparison to YM155-sensitive MPM cells. Despite this, an exosome inhibitor (GW4896) did not enhance MPM cell sensitivity to YM155. Additionally, our study showed no evidence of a correlation between the mRNA expression of inhibitor of apoptosis (IAP) gene family members and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in the MPM cell lines and correlated with poor sensitivity to YM155.

Comments:

The study focuses on finding ways to enhance the sensitivity of malignant pleural mesothelioma (MPM) cells to chemotherapy and specific small molecule inhibitors. The current treatment options for MPM are limited, and chemotherapy is commonly used as a first-line therapy for patients with unresectable MPM. However, drug resistance poses a challenge to its effectiveness.

The study found that transfection of certain microRNAs (miRNAs) into MPM cell lines resulted in a modest improvement in cell sensitivity to chemotherapy drugs. However, not all tested miRNAs had the same effect. On the other hand, the sensitivity to a small molecule inhibitor targeting FAK (PND-1186) was more significantly enhanced, consistent with previous research.

The researchers also investigated the response of MPM cells to a small molecule inhibitor called YM155, which targets survivin. Interestingly, they found that the response to YM155 was unrelated to the baseline expression of survivin. However, when YM155-resistant MPM cells were transfected with miRNAs, their sensitivity to YM155 treatment improved. This suggests that miRNAs could potentially overcome resistance to YM155 in MPM cells.

Furthermore, the study revealed that YM155-resistant MPM cells secrete a higher level of exosomes compared to YM155-sensitive MPM cells. However, inhibiting exosome production using GW4896 did not enhance MPM cell sensitivity to YM155. This indicates that the mechanism by which miRNAs enhance YM155 sensitivity might not involve exosomes.

The study also examined the mRNA expression of genes belonging to the inhibitor of apoptosis (IAP) gene family. Interestingly, no correlation was found between the expression of IAP genes and MPM cell sensitivity to YM155. However, two drug transporter genes, ABCA6 and ABCA10, were upregulated in MPM cell lines and correlated with poor sensitivity to YM155. This suggests that these transporter genes might play a role in reducing the effectiveness of YM155 treatment.

In summary, the study demonstrated that transfection of certain miRNAs can enhance the sensitivity of MPM cells to chemotherapy and small molecule inhibitors. While the mechanism by which miRNAs improve YM155 sensitivity remains unclear, it does not seem to involve exosomes. The upregulation of drug transporter genes, specifically ABCA6 and ABCA10, appears to be associated with reduced sensitivity to YM155 in MPM cells. These findings contribute to a better understanding of potential strategies for overcoming drug resistance in MPM treatment.