Small mitochondria-targeting compound SMIP004 selectively eliminates therapy-induced senescent tumor cells by blocking AMPK-dependent PDHA stabilization and improves the outcomes of chemotherapy

Abstract Therapy-induced senescence (TIS) contributes to tumor recurrence and metastasis. Selective elimination of TIS cells by senolytics would be beneficial for cancer treatment. Here, we found that the stabilization of PDHA (catalytic subunit of pyruvate dehydrogenase) in TIS cancer cells relies on the elevated activity of AMPK. A small-scale chemical screening in TIS cells identified SMIP004, a mitochondria-targeting compound, that can attenuate the PDHA stabilization by promoting the ubiquitin-mediated degradation of PDHA without affecting the activity of AMPK. Activation of AMPK by metformin also leads to the stabilization of ectopically expressed PDHA in proliferating cells, which can be attenuated by SMIP004 treatment or abolished by the substitution of AMPK phosphorylation sites on PDHA. Moreover, a low dose of SMIP004 exerts a selective killing of TIS cancer cells by inducing an energy crisis and massive apoptosis. Most importantly, SMIP004 combined with doxorubicin can suppress tumor growth, eliminate p21-positive cells, and reduce metastatic lesions in tumor-bearing mice. scRNA-seq analysis revealed that elevated transcription of PDHA is associated with senescence-like tumor cells. The expression of both PDHA and p21 is enhanced by chemotherapy and correlates with poor patient survival, implicating the therapeutic potential of targeting PDHA. As such, our findings demonstrated SMIP004 is a promising senolytic agent capable of selectively eliminating TIS cells by blocking the AMPK-mediated stabilization of PDHA.