Autophagy Blockade Sensitizes Prostate Cancer Cells towards Src Family Kinase Inhibitors

Abstract

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.

Autophagy as a mediator of chemotherapy-induced cell death in cancer

“…Examples for a key role of autophagy in chemoresistance are numerous when DNA damaging agents are used: camptothecin in breast cancer cells [61]; cisplatin in esophageal squamous cell carcinoma cells [62], in metastatic skin carcinomas [63] and in lung adenocarcinoma cells [64]; and 5-fluorouracil in colon cancer cells [65] and in esophageal cancer cells [66]. Similar observations were obtained with the new generation drugs: proteasome inhibitors [67,68], Src kinase inhibitor [69] and anti-HER2 monoclonal antibody [70] are such examples.…”

“…Chloroquine has indeed been shown to potentiate the anticancer effects of different drugs both in vitro and in vivo. It is the case for 5-fluorouracil in colon cancer cells [87], in a Myc-induced lymphoma mouse model treated with alkylating agents [88], in mouse models of prostate cancer treated with Src kinase inhibitor [69], or for imatinib-refractory chronic myeloid leukemia cells in combination with the HDAC inhibitor SAHA (suberoylanilide hydroxamic acid) [89]. Current phase I/II clinical trials are underway for evaluating the potential benefit of chloroquine in combination with conventional therapy for a variety of malignancies [73].…”

Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate-Resistant Prostate Cancer

“…These data are of interest in light of a previous study where knockdown of p130Cas, which signals downstream of FAK, resulted in enhanced autophagy in ovarian cancer cells (43) and add further weight to the emerging concept that the role of autophagy in cancer development and progression is highly context dependent. Thus, while specific autophagy genes, such as Beclin-1, can act as tumor suppressors (44), and particular drug regimens can exert cytotoxicity through autophagic cell death (45,46) induction of autophagy can also confer drug resistance to cancer cells, for example, against the TKIs erlotinib (47) and saracatinib (48). Moreover, our work also emphasizes how FAK signaling can exert contrasting effects on autophagy and cell survival.…”

Autophagy in colorectal cancer: An important switch from physiology to pathology

“…A combination of the autophagy inhibitor CQ and vorino stat, a histone deacetylase inhibitor, was shown to significantly reduce tumor growth and induce apoptosis in a colon cancer xenograft model [126] . Notably, the combination of CQ with saracatinib, an inhibitor of Src nonreceptor tyrosine kinase, enhanced apoptotic cell death and resulted in 64% tumor growth inhibition compared with saracatinib alone [127] . Autophagy inhibitors shown synergy with proteasome inhibitors; for example, the simultaneous use of bortezomib and CQ in a colon cancer xenograft model decreased tumor growth to a greater extent than the use of either of these drugs alone [128] .…”