Regulation of PI3K signaling in cancer metabolism and PI3K-targeting therapy

The phosphatidylinositol-3-kinase (PI3K) signaling plays a key role in various cellular functions and is frequently activated in cancer, making it an attractive therapeutic target. The PI3K signaling pathway influencing glucose metabolism, lipid synthesis, nucleotide production, and protein synthesis, all of which contribute to cancer cell proliferation and survival. It enhances glucose uptake through the activation of glucose transporters and glycolysis, while also promoting lipid synthesis via downstream factors like mTORC1. This pathway boosts nucleotide synthesis by regulating transcription factors like MYC, activating key enzymes for purine and pyrimidine production. Additionally, due to its essential role in cancer cell growth, the PI3K pathway is a key target for anticancer therapies. However, treatment using PI3K inhibitors alone has limitations, including drug resistance and significant side effects such as hyperglycemia, fatigue, and liver dysfunction. Clinical trials have led to the development of isoform-specific PI3K inhibitors to reduce toxicity. Combining PI3K inhibitors with other treatments, such as hormone therapy or surgery, may improve efficacy and minimize side effects. Further research is needed to fully understand the mechanisms of PI3K inhibitors and improve individualized treatment approaches. In this review, we introduce the characteristic of three classes of PI3Ks, discuss the regulation of cancer metabolism including the control of glucose uptake, glycolysis, de novo lipid synthesis, nucleotide synthesis and protein synthesis, and review the current statuses of different PI3K inhibitors therapy.