I3C, indole-3-carbinol, a major antitumor effect is to induce G1 phase arrest in tumor cells. This has been demonstrated in human prostate cancer cells, breast cancer cells, and keratinocyte cancer cells. I3C inhibits cell growth by regulating genes related to cell growth, including down-regulation of cyclins D1, E, cyclin-dependent kinases 2 and 6 (CDK 2, CDK6), and up-regulation of the expression of cyclin-dependent kinase inhibitors p15, p16, p21, and p27 to induce G1 arrest in cancer cells and inhibit tumor cell proliferation. In different tumor cells, I3C can regulate cyclin-dependent kinases, but the specific factors are different.
Induction of tumor cell apoptosis is another major antitumor effect of I3C. I3C induces apoptosis by downregulating the anti-apoptotic gene products Bcl-2, Bcl-xL, survivin, inhibitor of apoptosis protein (IAP), X chromosome-associated IAP (XIAP) and Fas-associated death domain protein-like Interleukin-1-converting enzyme inhibitory protein (FLIP), up-regulates the pro-apoptotic protein Bax; releases mitochondrial cytochrome C, activates caspase 9 and caspase-3 pathways and other pathways. Many responses were highly dependent on the cellular environment, suggesting different mechanisms underlying growth inhibition.
The phosphoinositide 3-kinase/serine-threonine kinase (PI3K/Akt) pathway is a major branch of the receptor tyrosine kinase pathway and is an important growth factor pathway in the body, which can activate anti-apoptotic mechanisms and promote Processes such as glucose metabolism and protein synthesis, thereby promoting cell growth and proliferation. PI3Ks are divided into type I, type II, and Type II. The most widely studied type I PI3K, which can be activated by cell surface receptors, is divided into two subtypes, IA and IB, which transmit signals from tyrosine-protein kinase-coupled receptors and G protein-coupled receptors, respectively. Among them, PI3K IA type is a heterodimer composed of catalytic subunit P110 and regulatory subunit P85 and has dual activities of phosphatidylinositol kinase and serine-threonine protein kinase. The catalytic subunit has 3 isoforms of p1 10a, pl 10β and p110δ encoded by 3 different genes, the regulatory subunit is encoded by 3 genes, and there are 5 isoforms such as p85a, p85β, p55y, p55a, and p50a, Among them, p85 is a phospholipid protein substrate of many receptor tyrosine kinases. In resting cells, the p85-p1 10 heterocomplex exists in the cytoplasm and is inactive.
Akt (also known as protein kinase B, PKB) is a serine/threonine-protein kinase that belongs to the AGC protein kinase superfamily and exists in three isoforms: Akt1/PKBa, Akt2/PKBβ, and Akt3/PKBγ. These three types are derived from different genes and have common features: ①N-terminal is the homology domain of plectrinin, containing a 3-phosphoinositide binding region similar to other signaling molecules; ②central kinase domain, which is highly related to PKA and PKC. Similarly, position 308 of this region contains threonine necessary for partial activation of Akt; ③ C-terminal is a regulatory domain carrying a phosphorylation site of the hydrophobic motif (CHM), and position 473 of this region contains Serine necessary for full activation of Akt. Akt is a direct target protein downstream of PI3K.
Abnormal activation of the PI3K/Akt signaling pathway occurs in many malignant tumors. The clearer mechanisms include (1) tyrosine kinase-mediated activation of PI3K, such as the binding of phosphorylated tyrosine kinase to subunit p85, or the direct binding of mutant Ras to PI3K, resulting in the activation of PI3K; (2) Somatic gene mutations, such as mutations in the PTEN tumor suppressor gene, prevent the PI3K pathway from being shut down, and PIK3CA gene mutations have recently been found to be present in 30% of epithelial tumors; the aforementioned tyrosine kinase-mediated abnormal activation of PI3K and somatic Gene mutations can lead to abnormal cell proliferation and cause tumors, such as ovarian cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, and other malignant tumors.
The PI3K/Akti pathway is considered to be the primary pathway for cancer cell survival, and is known as the "anti-apoptotic pathway". Various oncogene tyrosine kinase receptors, such as Src, Ras, Rac, Abl, etc., can activate PI3K. Phosphorylated PI3K produces phosphatidylinositol 4,5-biphosphate (PIP3) on the cell membrane. PIP3 causes Akt to be activated sequentially by phosphoinositide-dependent kinases 1 and 2 (PDK1 and PDK2), resulting in the transfer of Akt from the cytoplasm to the cytoplasmic membrane, phosphorylating Akt at Thr308, Ser473, and fully activating Akto in human tumors, Abnormal activation of Akt means an abnormal increase in growth, proliferation, metabolism and anti-apoptotic effects of tumor cells.
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