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Identification of a novel minor-groove DNA binder that represses mitochondrial genes expression and induces apoptosis in highly aggressive leiomyosarcoma cells

ABSTRACT: The induction of cellular stress is a common strategy in cancer therapy. Leiomyosarcomas (LMS) are aggressive tumors for which there are few effective therapeutic options. Through a combination of in silico and in vitro screens, the compound NSC-260594/XMH95 was identified as a promising molecule that selectively induces apoptosis in aggressive LMS cells. This apoptotic response is associated with the upregulation of the BH3-only genes PMAP1/NOXA, BIK, HRK and BBC3/PUMA. XMH95 binds DNA and possibly the minor groove, similar to Hoechst 33258. Unlike Hoechst, XMH95 is not fluorescent but can be photoactivated by UV irradiation when bound to DNA. Also, unlike Hoechst, XMH95 suppresses mitochondrial gene expression and is a more effective inducer of apoptosis. Apart from suppressing mitochondrial genes, XMH95 has many effects on gene expression that are common to Hoechst. Using an inhibitor of mitochondrial RNA polymerase (POLRMT), we show that XMH95 triggers apoptosis by perturbing both nuclear and mitochondrial transcription. Our results propose a new compound and a novel stress that can trigger apoptosis in aggressive cancer cells by upregulating multiple BH3-only genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288920 | GEO | 2025/10/14

REPOSITORIES: GEO

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Proteotoxic stress-induced apoptosis in cancer cells: understanding the susceptibility and enhancing the potency

Project description:Leiomyosarcoma (LMS) is an aggressive cancer with few therapeutic options. LMS cells are more sensitive to proteotoxic stress compared to normal smooth muscle cells. We used small compound 2c to induce proteotoxic stress and compare the transcriptomic adaptations of immortalized human uterine smooth muscle cells (HUtSMC) and LMS cells SK-UT-1. We found that the expression of the heat shock proteins (HSP) gene family is upregulated with higher efficiency in normal cells. In contrast, upregulation of BH3-only proteins is higher in LMS cells. HSF1, the master regulator of HSP transcription, is sequestered into transcriptionally incompetent nuclear foci only in LMS cells, which explains the lower HSP upregulation. We also found that several compounds can enhance the cell death response to proteotoxic stress. Specifically, when low doses were used, an inhibitor of salt-inducible kinases (SIKs) and the inhibitor of IRE1, a key element of the unfolded protein response (UPR), support proteotoxic-induced cell death with strength in LMS cells and without effects on the survival of normal cells. Overall, our data provide an explanation for the higher susceptibility of LMS cells to proteotoxic stress and suggest a potential option for co-treatment strategies.

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