Kaempferol modulates ɑ2M secretion in bone marrow-derived macrophages by downregulating GR/PER1-mediated lipid metabolism to attenuate the emotional stress-aggravated metastasis of prostate cancer.

Ethnopharmacological Relevance: Prostate cancer patients often suffer from depression during androgen deprivation therapy. Chaihu-Shugan-San (CSS) can prevent prostate cancer metastasis caused by chronic unpredictable mild stress (CUMS), but its active ingredients and molecular mechanism remain unelucidated.

Aim Of Study: This study aims to explore the potential targets and molecular mechanisms of CSS in the treatment of emotional stress-aggravated metastasis of prostate cancer.

Results: Stress induces nuclear translocation of GR, initiating the transcription of PER1, which leads to an enhanced lipid metabolism and decreased secretion of α2M in BMDMs. CSS, a classical Traditional Chinese Medicine (TCM) formula for alleviating depression, can improve prostate cancer metastasis caused by CUMS. Of the active ingredients in CSS, kaempferol demonstrated the highest potency for enhancing α2M secretion in BMDMs and inhibiting prostate cancer cell migration. Kaempferol also inhibited nuclear translocation of GR and the GR/PER1 pathway in Per1-overexpressed BMDMs.

Conclusions: These findings reveal that emotional stress-aggravated prostate cancer growth and metastasis rely on the GR/PER1 pathway and lipid metabolism, as the suppression of this pathway ultimately leads to an increase in α2M secretion in BMDMs and inhibition of PC-3 cell metastasis.