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.

Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors.

BackgroundBreast cancer is the most common cancer in women and several perioperative factors may account for tumor recurrence and metastasis. The anesthetic agents employed during cancer surgery might play a crucial role in cancer cell survival and patient outcomes. We conducted a retrospective cohort study to investigate the relationship between the type of anesthesia and overall survival in patients who underwent breast cancer surgery performed by one experienced surgeon.MethodsAll patients who underwent breast cancer surgery by an experienced surgeon between January 2006 and December 2010 were included in this study. Patients were separated into two groups according to the use of desflurane or propofol anesthesia during surgery. Locoregional recurrence and overall survival rates were assessed for the two groups (desflurane or propofol anesthesia). Univariable and multivariable Cox regression models and propensity score matching analyses were used to compare the hazard ratios for death and adjust for potential confounders (age, body mass index, American Society of Anesthesiologists physical status classification, TNM stage, neoadjuvant chemotherapy, Charlson Comorbidity Index, anesthesiologists, and functional status).ResultsOf the 976 breast cancer patients, 632 patients underwent breast cancer surgery with desflurane anesthesia, while 344 received propofol anesthesia. After propensity scoring, 592 patients remained in the desflurane group and 296 patients in the propofol group. The mortality rate was similar in the desflurane (38 deaths, 4%) and propofol (22 deaths, 4%; p = 0.812) groups in 5-year follow-up. The crude hazard ratio (HR) for all patients was 1.13 (95% confidence interval [CI] 0.67–1.92, p = 0.646). No significant difference in the locoregional recurrence or overall 5-year survival rates were found after breast surgery using desflurane or propofol anesthesia (p = 0.454). Propensity score-matched analyses demonstrated similar outcomes in both groups. Patients who received propofol anesthesia had a higher mortality rate than those who received desflurane anesthesia in the matched groups (7% vs 6%, respectively) without significant difference (p = 0.561). In the propensity score-matched analyses, univariable analysis showed an insignificant finding (HR = 1.23, 95% CI 0.72–2.11, p = 0.449). After adjustment for the time since the earliest included patient, the HR remained insignificant (HR = 1.23, 95% CI 0.70–2.16, p = 0.475).ConclusionIn our non-randomized retrospective analysis, neither propofol nor desflurane anesthesia for breast cancer surgery by an experienced surgeon can affect patient prognosis and survival. The influence of propofol anesthesia on breast cancer outcome requires further investigation.