PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.

Background: Breast cancer is the leading cause of cancer death among women worldwide and metastasis is the major cause of treatment failure. Thus, new treatment options for breast cancer, especially, drugs which could prevent metastasis, are pressingly needed. Methods: In the present study, we designed and synthesized a novel cinnamide derivative, (E)-N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-3-(3,4,5-trimethoxyphenyl)acrylamide (YLT26), which displayed potent inhibitory effects on breast cancer cells. The cell viability, apoptosis-inducing effect and reactive oxygen species (ROS) production were examined in 4T1 cells following treatment with YLT26. Meanwhile, apoptosis-related proteins levels were determined by western blotting. Finally, we evaluated the effects of YLT26 on breast tumor growth, lung metastases in vivo and the infiltration of myeloid-derived suppressor cells (MDSCs) in lung tissue. Results: Our results showed that the proliferation inhibitory effects of YLT26 were correlated with its apoptosis-inducing effect. Exposure to YLT26 induced mitochondrial transmembrane potential (∆Ψm) change, activated caspase-9, and downregulated the Bcl-2 expression, as well as enhanced ROS accumulation in 4T1 cells. Moreover, YLT26 significantly inhibited tumor growth without obvious side effects in the 4T1 tumor-bearing mice model. Immunohistochemistry analyze revealed YLT26 also induced apoptosis in vivo. More importantly, YLT26 also significantly inhibited lung metastases, which may be associated with the reduction of MDSCs. Conclusion: The present study suggested that YLT26 could inhibit breast cancer cells proliferation via ROS-mitochondrial apoptotic pathway, delay breast tumor progression, and suppress lung metastases by impacting on the immunologic microenvironment in vivo.

Background: RACGAP1 has significant involvement in tumorigenesis of cancers, including liver cancer, stomach cancer, and colon cancer. However, the role and the exact mechanism of RACGAP1 in esophageal squamous cell carcinoma (ESCC) has not been explored.Methods: QPCR and Western blots analysis was performed to analyze the expression of RACGAP1 in ESCC. MTT assays and colony formation assays were performed to explore the functional role of RACGAP1 in ESCC. Cell cycle analysis and immunofluorescence assays were used to investigate the function of RACGAP1 involvement in mitotic catastrophe. At last, we conducted the public datasets mining to explore the expression status and prognosis value of RACGAP1 as well as the correlation between RACGAP1 and E2F3 in various cancers. Results:The high abnormal expression of RACGAP1 is observed in ESCC and associated with worse clinical outcomes of patients with ESCC. RACGAP1, a novel cell cycle associated gene regulated by E2F3, acts as an oncogenic driver in ESCC cell lines. Notably, for the first time, RACGAP1 depletion induced severe mitotic catastrophe, followed by massive cell death.Conclusions: Our findings showed the essential role of RACGAP1 in ESCC cancer cell survival and the therapeutic potential of RACGAP1 as a molecular target for ESCC.

1 0 PPP metabolites promote AKT activation by negatively regulating