TY - JOUR
T1 - Blockade of ACK1/TNK2 to Squelch the Survival of Prostate Cancer Stem-like Cells
AU - Mahajan, Nupam P.
AU - Coppola, Domenico
AU - Kim, Jongphil
AU - Lawrence, Harshani R.
AU - Lawrence, Nicholas J.
AU - Mahajan, Kiran
N1 - Funding Information:
We would like to thank Thanh Nguyen, Duy Nguyen and Devon DeLoach for technical assistance. This work was supported in part by Department of Defense award W81XWH-14-1-0251 to K.M. and by the National Cancer Institute, NIH (1R01CA135328; 5R01CA208258), Department of Defense (W81XWH-14-1-0002, W81XWH-14-1-0003), Bankhead-Coley (6BC08) and Miles for Moffitt grant (09-33661-15-13) to N.P.M. This work was supported in part by the Core Facilities at Moffitt Cancer Center and by Cancer Center Support Grant P30 CA076292.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041311367&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-20172-z
DO - 10.1038/s41598-018-20172-z
M3 - Article
C2 - 29386546
AN - SCOPUS:85041311367
SN - 2045-2322
VL - 8
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 1954
ER -