Phosphatase LHPP confers prostate cancer ferroptosis activation by modulating the AKT-SKP2-ACSL4 pathway
》》Journal：Cell Death Dis .
》》相关产品：RGFP966 (SJ-MX0358) 和 MK-2206 dihydrochloride (SJ-MX0056)
》》产品引用描述：
》》Abstract
LHPP, a novel, recognized tumor suppressor, exerts a critical influence on the regulation of tumor cell proliferation and survival by modulating various signaling pathways with its phosphatase activity. Here, we unveil a robust correlation between reduced LHPP expression and adverse prognosis in prostate cancer. We demonstrate that LHPP interacts with AKT, thereby dampening AKT phosphorylation and subsequently inhibiting ACSL4 phosphorylation at the T624 site. This interaction impedes phosphorylation-dependent ubiquitination, thwarting SKP2 from recognizing and binding to ACSL4 at the K621 site. As a result, ACSL4 is spared from lysosomal degradation, leading to its accumulation and the promotion of lipid peroxidation, and ferroptosis. Moreover, our findings reveal that Panobinostat, a potent histone-deacetylase inhibitor, intricately regulates LHPP expression at multiple levels through the inhibition of HDAC3. This complex modulation enhances the ferroptosis pathway, offering a novel mechanism for curtailing the growth of prostate tumors and highlighting its significant translational potential for clinical application.
》》部分文献数据展示：
Fig 3. F Western blot analysis of ACSL4 and p-AKT (S473) levels in control and LHPP knockdown cells treated with the AKT inhibitor MK2206 (5 μM) for 24 h. G Western blot analysis of endogenous Co-IP revealed an interaction between ACSL4 and AKT. H Immunofluorescence analysis of co-localization of ACSL4 and AKT in DU145 and C4-2B cells. I Western blot analysis and Coomassie Bright Blue staining of GST pull-down of GST-tagged AKT1 binding with ACSL4 in vitro. J Western blot analysis of ACSL4 expression after AKT1 overexpression and treatment with MK2206 (5 μM) for 24 h. K RT qPCR analysis of ACSL4 mRNA after treatment with MK2206 (5 μM) or SC79 (10 μM) for 24 h.
