Autophagy Blockade Sensitizes Prostate Cancer Cells towards Src Family Kinase Inhibitors.
There is overwhelming evidence that tyrosine kinases play an important role in cancer development. As a prototype of targeted therapy, tyrosine kinase inhibitors are now successfully applied to cancer treatment. However, as single agents, tyrosine kinase inhibitors have not achieved satisfactory results in the treatment of prostate cancer, principally due to their inability to efficiently kill tumor cells. The authors' laboratory has been interested in the role of the Src complex in prostate cancer progression, including the induction of androgen independence and metastasis. Previously, the authors reported that Src inhibitors such as saracatinib and PP2 caused G1 growth arrest and diminished invasiveness in prostate cancer cells but rarely apoptosis. Here, they have shown that Src family kinase (SFK) inhibitors can induce a high level of autophagy, which protects treated cells from undergoing apoptosis. Src siRNA knockdown experiments confirmed that autophagy was indeed caused by the lack of Src activity. The SFK inhibitor-induced autophagy is accompanied by the inhibition of the PI3K (type I)/Akt/mTOR signaling pathway. To test whether autophagy blockade could lead to enhanced cell death, pharmacological inhibitors (3-methyladenine and chloroquine) and a genetic inhibitor (siRNA targeting Atg7) were used in combination with SFK inhibitors. The results showed that autophagy inhibition effectively enhanced cell killing induced by SFK inhibitors. Importantly, the authors showed that a combination of saracatinib with chloroquine in mice significantly reduced prostate cancer (PC3) xenograft growth compared with the control group. Taken together, these data suggest that (1) autophagy serves a protective role in SFK inhibitor-mediated cell killing, and (2) clinically acceptable autophagy modulators may be used beneficially as adjunctive therapeutic agents for SFK inhibitors.
Wu
Zhaoju
Z
Department of Biological Chemistry and Molecular Medicine.
Chang
Pei-Ching
PC
Yang
Joy C
JC
Chu
Cheng-Ying
CY
Wang
Ling-Yu
LY
Chen
Nien-Tsu
NT
Ma
Ai-Hong
AH
Desai
Sonal J
SJ
Lo
Su Hao
SH
Evans
Christopher P
CP
Lam
Kit S
KS
Kung
Hsing-Jien
HJ
Leukemia. 2007 May;21(5):926-35
17330101
Anticancer Res. 2007 Mar-Apr;27(2):1095-104
17465249
Mol Cell Biol. 2001 Dec;21(24):8385-97
11713275
Blood. 2006 Jun 1;107(11):4532-9
16469872
J Biol Chem. 1995 Feb 3;270(5):2320-6
7836465
Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3644-9
9520419
Nature. 2008 Feb 28;451(7182):1069-75
18305538
Nat Rev Mol Cell Biol. 2007 Sep;8(9):741-52
17717517
Urol Oncol. 2009 Jan-Feb;27(1):48-52
19111798
Crit Rev Clin Lab Sci. 2009;46(4):210-40
19552522
Nat Rev Cancer. 2004 Jun;4(6):470-80
15170449
Oncogene. 2004 Mar 18;23(12):2197-205
14767470
J Clin Invest. 2008 Jan;118(1):79-88
18097482
Mol Cell Biol. 1994 Mar;14(3):1680-8
7509446
Oncogene. 2004 Apr 12;23(16):2891-906
15077152
Oncogene. 2008 Oct 23;27(49):6365-75
18679417
Curr Opin Pharmacol. 2008 Aug;8(4):427-32
18625340
BJU Int. 2009 Feb;103(4):434-40
19154462
Oncogene. 2007 Feb 1;26(5):745-56
16862179
CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
19474385
Drugs. 2009 Nov 12;69(16):2303-28
19852530
Cancer Res. 2009 Jan 1;69(1):151-60
19117998
Neoplasia. 2007 Feb;9(2):90-100
17357254
Cell Death Differ. 2005 Nov;12 Suppl 2:1509-18
16247498
Nat Cell Biol. 2000 May;2(5):249-56
10806474
Cancer Res. 2006 Jun 1;66(11):5542-8
16740687
J Bone Miner Res. 2010 Mar;25(3):463-71
19775203
Cancer Res. 2006 Oct 15;66(20):10040-7
17047067
Cancer Res. 2009 Sep 15;69(18):7402-11
19706771
Cancer Res. 2005 Jun 15;65(12):5358-64
15958584
Clin Cancer Res. 2007 Dec 15;13(24):7232-6
18094400
Cancer Cell. 2004 Sep;6(3):209-14
15380511
Ann Oncol. 2008 Aug;19(8):1379-1386
18487549
Cancer Cell. 2006 Oct;10(4):309-19
17045208
Cancer Res. 2009 Jan 15;69(2):700-8
19147587
Autophagy. 2009 Nov;5(8):1131-44
19786832
BJU Int. 2009 Jan;103(2):171-7
18990162
Blood. 2007 Jul 1;110(1):313-22
17363733
J Cell Biol. 2005 Nov 21;171(4):603-14
16286508
Prostate Cancer Prostatic Dis. 2007;10(2):185-8
17211440
Clin Cancer Res. 2009 May 15;15(10):3540-9
19447874
J Clin Invest. 2009 May;119(5):1109-23
19363292
Proc Natl Acad Sci U S A. 1982 Mar;79(6):1889-92
6952238
Clin Ther. 2007 Nov;29(11):2289-308
18158072
J Cell Sci. 2004 Nov 1;117(Pt 23):5479-87
15509864
Curr Top Dev Biol. 2007;78:217-45
17338918
Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10148-52
7937853
Mol Cancer Ther. 2009 Feb;8(2):394-406
19190119
EMBO J. 2000 Nov 1;19(21):5720-8
11060023
Cancer Res. 2005 Aug 15;65(16):7214-22
16103072
Mol Oncol. 2009 Aug;3(4):366-75
19559660
Anticancer Drugs. 2009 Mar;20(3):179-84
19396016
Cancer Res. 2008 Dec 1;68(23):9624-33
19047139
J Clin Invest. 2007 Feb;117(2):326-36
17235397
Mol Biol Cell. 1999 May;10(5):1367-79
10233150
Breast Cancer Res Treat. 2007 Nov;105(3):319-26
17268817
Nat Rev Cancer. 2007 Dec;7(12):961-7
17972889
Autophagy. 2007 Sep-Oct;3(5):464-7
17495516
Int J Biochem Cell Biol. 2004 Dec;36(12):2503-18
15325588
Nat Rev Clin Oncol. 2009 Oct;6(10):587-95
19787002
Cancer Res. 2008 May 1;68(9):3323-33
18451159