Mcl-1 proteins and their relation with senolytic therapy
Mcl-1 (Induced myeloid leukemia cell differentiation protein) is a protein that is encoded by the MCL1 gene in humans.
Cells subjected to treatment with anti-cancer therapies can evade apoptosis through cellular senescence.
Persistent senescent tumor cells remain metabolically active, possess a secretory phenotype, and can promote tumor proliferation and metastatic dissemination.
Removal of senescent tumor cells (senolytic therapy) has therefore emerged as a promising therapeutic strategy.
Here, using single-cell RNA-sequencing, we find that senescent tumor cells rely on the anti-apoptotic gene Induced myeloid leukemia cell for their survival.
Mcl-1 is upregulated in senescent tumor cells, including cells expressing low levels of Bcl-2 (B-cell lymphoma 2), an established target for senolytic therapy.
While treatment with the Bcl-2 inhibitor Navitoclax results in the reduction of metastases in tumor bearing mice, treatment with the Induced myeloid leukemia cell inhibitor S63845 leads to complete elimination of senescent tumor cells and metastases.
These findings provide insights on the mechanism by which senescent tumor cells survive and reveal a vulnerability that can be exploited for cancer therapy.
Finally, senescent tumor cells share common features with aged cells.
If validated in other models, these findings could be relevant also to ameliorate aging and age-related pathologies.