Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C1519176 (
PSA
)
5,490
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Prostate cancer stem-like cells (PCSCs) are not only enriched in the CD44
+
PSA
-/lo
subpopulation but also employ androgen-independent signaling mechanisms for survival. CD44
+
PCSCs defy androgen deprivation, resist chemo- and radiotherapy and are highly tumorigenic. Human prostate tissue microarray (TMA) staining revealed an increased membranous staining of CD44 in the luminal compartment in higher grade G7-G9 tumors versus staining of the basal layer in benign hyperplasia. To uncover tyrosine kinase/s critical for the survival of the CD44
+
PSA
-/lo
subpopulation, we performed an unbiased screen targeting 87 tyrosine kinases with gene specific siRNAs. Among a subset of tyrosine kinases crucial for PCSC survival, was a non-receptor tyrosine kinase,
ACK1
/
TNK2
, a critical regulator of castration resistant prostate cancer (CRPC) growth. Consistently, activated
ACK1
as measured by phosphorylation at Tyr284 was significant in the CD44
+
PSA
-/lo
population. Conversely, pharmacological inhibition by
ACK1
inhibitor, (R)-9bMS mitigated CD44
+
PSA
-/lo
sphere formation, overcame resistance to radiation-induced cell death, induced significant apoptosis in PCSCs and inhibited CD44
+
PSA
-/lo
xenograft tumor growth in castrated mice suggesting dependency of PCSCs on
ACK1
for survival. Thus, blockade of
ACK1
/
TNK2
could be a new therapeutic modality to target recalcitrant PCSCs.
...
PMID:Blockade of ACK1/TNK2 To Squelch the Survival of Prostate Cancer Stem-like Cells. 2938 46
