Psoralidin, an herbal molecule, inhibits phosphatidylinositol 3-kinase-mediated Akt signaling in androgen-independent prostate cancer cells.
The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-kappaB and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.
Kumar
Raj
R
Department of Clinical Laboratory Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky, USA.
Srinivasan
Sowmyalakshmi
S
Koduru
Srinivas
S
Pahari
Pallab
P
Rohr
Jürgen
J
Kyprianou
Natasha
N
Damodaran
Chendil
C
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003374:Coumarins / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D028321:Plant Preparations / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D001572:Benzofurans; D003374:Coumarins; D028321:Plant Preparations; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C102768:psoralidin