Abstract
PTEN loss and constitutive activation of the PI3K signaling pathway have been associated with advanced androgen-independent prostate cancer. PTEN-deficient prostate cancer C42Luc cells survive in serum-free media and show relative resistance to apoptosis even in the presence of the PI3K inhibitor ZSTK474. Yet, when ZSTK474 is combined with the translation inhibitor cycloheximide, C42Luc cells undergo apoptosis within 6 hours. We identified dephosphorylation of BAD (Bcl2-associated death promoter) as a main apoptosis-regulatory molecule downstream from PI3K, and loss of MCL-1 (Myeloid cell leukemia -1) as a major target of cycloheximide. The combination of MCL-1 knockdown and expression of phosphorylation-deficient mutant BAD2SA is sufficient to trigger rapid apoptosis in prostate cancer cells. These results establish the mechanism for the synergistic induction of apoptosis by the combination of a PI3K inhibitor and of a protein synthesis inhibitor in PTEN-deficient prostate cancer cells.
Highlights
Several studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as one of the major factors in prostate carcinogenesis and progression to therapeutic resistance [1,2,3]
Mice with prostate-restricted PTEN knockout have reduced levels of apoptosis and diminished prostate involution upon castration [10]. These results suggest that constitutive activation of the PI3K pathway in PTEN-null advanced prostate tumors contributes to androgen independence by inhibiting apoptosis
The PI3K signaling pathway is constitutively activated in C42Luc prostate cancer cells due to a deletion of one allele of the lipid phosphatase PTEN and a frameshift mutation in the other allele [24]
Summary
Several studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as one of the major factors in prostate carcinogenesis and progression to therapeutic resistance [1,2,3]. PI3K serves as a mediator of intracellular signal transduction by generating phosphatidylinositol (3–5)-triphosphate (PIP3) through phosphorylation of phosphatidylinositol (4,5)-biphosphate (PIP2). PIP3 recruits proteins containing the pleckstrin homology (PH) domain (including AKT kinase) to the cellular membrane, where they undergo a conformational change. The lipid phosphatase and tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) serves as a negative regulator of Akt and the PI3K pathway by dephosphorylating PIP3 and converting it back to PIP2. The primary mechanism for PI3K dysregulation is the loss of function of PTEN through homozygous deletions, loss of heterozygosity, or inactivating mutations [6,7], leading to the constitutive activation of Akt
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call