Loss of tumor suppressors during cell transformation correlates with tumor progression, cell phenotype changes and metastases. This leads to therapy-resistance, dysregulation of chemokine-mediated signaling, increased tumor cell migration and invasion, and markedly lower patient survival.
Tumor suppressors such as PTEN, Egr-1 and protein phosphatase 2 (PP2A) play an important role in the progression of metastatic therapy-resistant tumors. As tumors progress and become resistant to therapy, PTEN is downregulated or mutated, Egr-1 expression is downregulated and PP2A becomes inactive. Drugs like thioridazine has been shown to markedly restore the expression or activity of the tumor suppressor PTEN, the transcription factor Egr-1, the Forkhead transcription factor FOXO, and PP2A .
Phenothiazines, such as thioridazine have been found to activate PP2A, cause dephosphorylation of key PP2A substrates in several oncolytic pathways and cell death. It has been reported that these phenothiazine compounds bind directly to the PP2A-α subunit and cause PP2A activation in tumor cells. Several mechanisms have been proposed to explain the pervasive inhibition of serine/threonine kinase signaling by phenothiazines; however, the structural basis and effects on PP2A phosphatase activity have not yet been established.
Thioridazine is a cyclin-dependent kinase CDK4 inhibitor. Published studies have shown that CDK4 plays an important role in the growth and cell cycle progression in several therapy-resistant cancers, and that thioridazine arrests these cells at this G1/G0 phase of the cell cycle. Studies have also shown that thioridazine down-regulates Cyclin D1, Cyclin A, CDK4, p-4EBP1, and unbound eIF4A; and upregulates the cyclin-dependent kinase inhibitors and the tumor suppressors p21waf/cip1 and p27kip1 resulting in apoptosis.
The dephosphorylation and nuclear relocation of the FOXO transcription factor occurs after activation of PTEN by thioridazine. This, in turn, upregulates the p21waf/cip1 and p27kip1 tumor suppressors. The p21waf/cip1 and p27kip1 tumor suppressors inhibit the interaction of cyclin D1 with the cyclin-dependent kinase CDK4 in normal cells. CDK4 is a kinase that, together with cyclin D1 and functional pRb, facilitates the transition of dividing cells from the G1 to the S (synthesis) phase of the cell cycle. Studies have shown that in tumors containing breast cancer cells, glioblastoma cells and melanoma cells, the cells rely on CDK4 for division and growth. Downregulated expression or loss of nuclear p27kip1 has been reported in several types of cancer, including breast cancer, melanoma, glioblastoma, lung cancer and pancreatic cancer. Studies have shown that restoration of p21waf/cip1 and p27kip1 through nuclear relocation of the FOXO transcription factor reduces cyclin D1 and inhibits CDK4 activity. This results in arrest of these cells at this G1/S phase checkpoint and the re-activation of apoptosis.
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