Shuping Xu1, Zhang Weihua. 1. Department of Urology, University of Pittsburgh Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Abstract
BACKGROUND: The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is over-expressed in advanced prostate cancer but tyrosine kinase inhibitors are not clinically effective in the treatment of prostate cancer. Recently it was found that EGFR in cancer cells has a kinase-independent pro-survival function, preventing cells from undergoing autophagy. In the present study we investigated whether the anti-autophagic function of EGFR may contribute to resistance of hormone-refractory prostate cancer cells to chemotherapeutic-induced apoptosis. METHODS: We first characterized the autophagic phenotype induced by knocking down EGFR in hormone refractory prostate cancer cells (PC-3MM2 and DU-145), then we tested whether loss of EGFR-induced autophagy could sensitize cancer cells to adriamycin. RESULTS: Using continuous live cell imaging techniques, we observed that knocking down EGFR lead to typical autophagic morphological/molecular changes, cell shrinkage without detachment, aggregation of microtubule-associated protein 1 light chain 3 (LC3) protein and absence of activation of apoptotic caspases 3/7. Loss of EGFR also increased the activity of calpain, which is pro-apoptotic. Knocking down EGFR, but not inhibiting its tyrosine kinase activity, significantly sensitized cells to adriamycin-induced apoptosis. Adriamycin-induced apoptosis could be inhibited by increased extracellular glucose level, suggesting intracellular glucose deficiency is a key mediator of the sensitization. The loss of EGFR induced autophagy and sensitization to adriamycin were also reproduced by using another hormone refractory prostate cancer cell line, Du145. CONCLUSION: Taken together, these data suggest that decreasing the expression level of EGFR protein, rather than inhibiting its tyrosine kinase activity, may enhance the efficiency of EGFR targeted therapy for prostate cancer. This article is a US Government work and, as such, is in the public domain in the United States of America. Published in 2011 Wiley-Liss, Inc.
BACKGROUND: The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is over-expressed in advanced prostate cancer but tyrosine kinase inhibitors are not clinically effective in the treatment of prostate cancer. Recently it was found that EGFR in cancer cells has a kinase-independent pro-survival function, preventing cells from undergoing autophagy. In the present study we investigated whether the anti-autophagic function of EGFR may contribute to resistance of hormone-refractory prostate cancer cells to chemotherapeutic-induced apoptosis. METHODS: We first characterized the autophagic phenotype induced by knocking down EGFR in hormone refractory prostate cancer cells (PC-3MM2 and DU-145), then we tested whether loss of EGFR-induced autophagy could sensitize cancer cells to adriamycin. RESULTS: Using continuous live cell imaging techniques, we observed that knocking down EGFR lead to typical autophagic morphological/molecular changes, cell shrinkage without detachment, aggregation of microtubule-associated protein 1 light chain 3 (LC3) protein and absence of activation of apoptotic caspases 3/7. Loss of EGFR also increased the activity of calpain, which is pro-apoptotic. Knocking down EGFR, but not inhibiting its tyrosine kinase activity, significantly sensitized cells to adriamycin-induced apoptosis. Adriamycin-induced apoptosis could be inhibited by increased extracellular glucose level, suggesting intracellular glucose deficiency is a key mediator of the sensitization. The loss of EGFR induced autophagy and sensitization to adriamycin were also reproduced by using another hormone refractory prostate cancer cell line, Du145. CONCLUSION: Taken together, these data suggest that decreasing the expression level of EGFR protein, rather than inhibiting its tyrosine kinase activity, may enhance the efficiency of EGFR targeted therapy for prostate cancer. This article is a US Government work and, as such, is in the public domain in the United States of America. Published in 2011 Wiley-Liss, Inc.
Authors: Justin S Gundara; JingTing Zhao; Anthony J Gill; James C Lee; Leigh Delbridge; Bruce G Robinson; Catriona McLean; Jonathan Serpell; Stan B Sidhu Journal: Cancer Med Date: 2014-12-08 Impact factor: 4.452