Haloperidol Instigates Endometrial Carcinogenesis and Cancer Progression by the NF-κB/CSF-1 Signaling Cascade

SIMPLE SUMMARY: Haloperidol, a typical antipsychotic, is widely used in schizophrenia and palliative care of cancer; however, the role and impact of chronic haloperidol treatment in endometrial cancer (EC) development are unclear. Here, we showed that haloperidol is a carcinogenic compound capable of inducing endometrial hyperplasia and promoting EC progression in rodents. Mechanistically, haloperidol stimulates the production of colony-stimulating factor 1 (CSF-1) on tumor cells by activating nuclear factor kappa B (NF-κB), and its downstream autocrine oncogenic CSF-1 receptor signaling contributes to this carcinogenesis. Furthermore, we demonstrated that the use of haloperidol is associated with increased EC-specific mortality in EC patients. Overall, these findings highlighted that physicians should be cautious about the use of haloperidol in female patients. ABSTRACT: Haloperidol is a routine drug for schizophrenia and palliative care of cancer; it also has antitumor effects in several types of cancer. However, the role of haloperidol in endometrial cancer (EC) development is still unclear. Here, we show that chronic haloperidol treatment in clinically relevant doses induced endometrial hyperplasia in normal mice and promoted tumor growth and malignancy in mice with orthotopic EC. The pharmacokinetic study indicated that haloperidol highly accumulated in the uterus of mice. In vitro studies revealed that haloperidol stimulated the cellular transformation of human endometrial epithelial cells (HECCs) and promoted the proliferation, migration, and invasion of human endometrial carcinoma cells (HECCs) by activating nuclear factor kappa B (NF-κB) and its downstream signaling target, colony-stimulating factor 1 (CSF-1). Gain of function of CSF-1 promotes the cellular transformation of HEECs and the malignant progression of HECCs. Moreover, blockade of CSF-1 inhibited haloperidol-promoted EC progression in vitro and in vivo. A population-based cohort study of EC patients further demonstrated that the use of haloperidol was associated with increased EC-specific mortality. Collectively, these findings indicate that clinical use of haloperidol could potentially be harmful to female patients with EC.