Gossypol Inhibits GLI3-dependent SHH Signaling to Selectively Target SPOP-deficient Breast Cancer Cells.
Breast cancer remains one of the leading causes of cancer-related mortality among women. The molecular heterogeneity of breast cancer, reflected in its numerous subtypes with variable responses to conventional and targeted therapies, necessitates the development of novel therapeutic strategies. Speckle-type POZ protein (SPOP), a substrate adaptor for Cul3-dependent ubiquitin ligase complexes, is frequently downregulated in breast cancer, yet the mechanisms linking SPOP loss to breast oncogenesis are poorly understood. This study aimed to elucidate the role of SPOP deficiency in breast cancer progression and identify potential therapeutic vulnerabilities associated with this molecular context.
MCF-7 breast cancer cells were subjected to SPOP knockdown to assess effects on cell proliferation and Sonic Hedgehog (SHH) signaling activity. A natural compound library was screened to identify agents selectively targeting SPOP-deficient cells. Candidate compounds were evaluated for effects on cell viability, GLI3 target gene expression, and clonogenic growth.
SPOP knockdown in MCF-7 cells increased proliferation and led to hyperactivation of GLI3-dependent SHH signaling. Screening of the natural compound library identified gossypol as a selective inhibitor of SPOP-deficient cells. Gossypol treatment significantly reduced cell viability, suppressed GLI3 target gene expression and impaired clonogenic growth in SPOP-deficient cells, while exerting minimal effects on control cells.
These findings identify a novel oncogenic role for SPOP loss in promoting breast cancer progression via GLI3-dependent SHH signaling. Furthermore, gossypol is highlighted as a potential targeted therapeutic agent for breast cancers characterized by SPOP deficiency.
MCF-7 breast cancer cells were subjected to SPOP knockdown to assess effects on cell proliferation and Sonic Hedgehog (SHH) signaling activity. A natural compound library was screened to identify agents selectively targeting SPOP-deficient cells. Candidate compounds were evaluated for effects on cell viability, GLI3 target gene expression, and clonogenic growth.
SPOP knockdown in MCF-7 cells increased proliferation and led to hyperactivation of GLI3-dependent SHH signaling. Screening of the natural compound library identified gossypol as a selective inhibitor of SPOP-deficient cells. Gossypol treatment significantly reduced cell viability, suppressed GLI3 target gene expression and impaired clonogenic growth in SPOP-deficient cells, while exerting minimal effects on control cells.
These findings identify a novel oncogenic role for SPOP loss in promoting breast cancer progression via GLI3-dependent SHH signaling. Furthermore, gossypol is highlighted as a potential targeted therapeutic agent for breast cancers characterized by SPOP deficiency.