Inhibition of both mesothelioma cell growth and Cdk4 activity following treatment with a TATp16INK4a peptide.
Disruption of the 9p21 locus is common in mesothelioma and leads to loss of both the p16INK4a and the p14ARF gene products. This study tested the hypothesis that reexpression of p16INK4a carried out using the TAT delivery system that carries the protein transduction domain of the HIV TAT will result in mesothelioma cell death.


METHODS
A synthetic TATp16INK4a peptide and a charge matched control were transduced into mesothelioma cells in vitro and in vivo. Cells were assayed for Cdk4 inhibition, cell cycle arrest, and cell death.


RESULTS
Treatment of mesothelioma cells with TATp16INK4a for 48 hours resulted in cell death. Apoptosis and G1 cell cycle arrest was also observed. Following transduction of cells with TATp16INK4a there was complete but transient hypophosphorylation of pRb. Similar effects were observed in mesothelioma xenografts.


CONCLUSIONS
Therapeutic strategies which introduce either TATp16INK4a peptide, or small molecule mimetic, could be an effective strategy for mesothelioma treatment.
Frizelle
Sandra P
SP
Research Service, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Kratzke
Marian G
MG
Carreon
Richard R
RR
Engel
Sean C
SC
Youngquist
Laura
L
Klein
Mark A
MA
Fourre
Laura
L
Shekels
Laurie L
LL
Kratzke
Robert A
RA
D000595:Amino Acid Sequence; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; D051358:Cyclin-Dependent Kinase 4