Glucose-6-phosphate dehydrogenase and transketolase: Key factors in breast cancer progression and therapy.

Breast cancer is one of the most common malignant tumors in women and is a serious threat to women's health. The pentose phosphate pathway (PPP) is a mode of oxidative breakdown of glucose that can be divided into oxidative (oxPPP) and non-oxidative (non-oxPPP) stages and is necessary for cell and body survival. However, abnormal activation of PPP often leads to proliferation, migration, invasion, and chemotherapy resistance in breast cancer. Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme in PPP oxidation. Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) produced by G6PD is the raw material for cholesterol and lipid synthesis and can resist the production of oxygen species (ROS) and reduce oxidative stress damage to tumor cells. Transketolase (TKT) is a key enzyme in non-oxPPP. Ribose 5-phosphate (R5P), produced by TKT, is a raw material for DNA and RNA synthesis, and is essential for tumor cell proliferation and DNA damage repair. In this review, we describe the role and specific mechanism of the PPP and the two most important enzymes of the PPP, G6PD and TKT, in the malignant progression of breast cancer, providing strategies for future clinical treatment of breast cancer and a theoretical basis for breast cancer research.

Human papillomavirus-16 E6 activates the pentose phosphate pathway to promote cervical cancer cell proliferation by inhibiting G6PD lactylation.

High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.

Lactylation stabilizes DCBLD1 activating the pentose phosphate pathway to promote cervical cancer progression.

BACKGROUND: Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple regulation of tumor progression, but specific mechanisms remain unclear in cervical cancer. Lactate-mediated lactylation modulates protein function. Whether DCBLD1 can be modified by lactylation and the function of DCBLD1 lactylation are unknown. Therefore, this study aims to investigate the lactylation of DCBLD1 and identify its specific lactylation sites. Herein, we elucidated the mechanism by which lactylation modification stabilizes the DCBLD1 protein. Furthermore, we investigated DCBLD1 overexpression activating pentose phosphate pathway (PPP) to promote the progression of cervical cancer. METHODS: DCBLD1 expression was examined in human cervical cancer cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of DCBLD1 on the progression of cervical cancer. Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics studies were used to characterize DCBLD1-induced metabolite alterations. Western blot, immunofuorescence and transmission electron microscopy were performed to detect DCBLD1 degradation of G6PD by activating autophagy. Chromatin immunoprecipitation, dual luciferase reporter assay for detecting the mechanism by which lactate increases DCBLD1 transcription. LC-MS/MS was employed to verify specific modification sites within the DCBLD1 protein. RESULTS: We found that lactate increased DCBLD1 expression, activating the PPP to facilitate the proliferation and metastasis of cervical cancer cells. DCBLD1 primarily stimulated PPP by upregulating glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. The mechanism involved the increased enrichment of HIF-1α in the DCBLD1 promoter region, enhancing the DCBLD1 mRNA expression. Additionally, lactate-induced DCBLD1 lactylation stabilized DCBLD1 expression. We identified DCBLD1 as a lactylation substrate, with a predominant lactylation site at K172. DCBLD1 overexpression inhibited G6PD autophagic degradation, activating PPP to promote cervical cancer progression. In vivo, 6-An mediated inhibition of G6PD enzyme activity, inhibiting tumor proliferation. CONCLUSIONS: Our findings revealed a novel post-translational modification type of DCBDL1, emphasizing the significance of lactylation-driven DCBDL1-mediated PPP in promoting the progression of cervical cancer.