Treatment-Induced Autophagy Associated with Tumor Dormancy and Relapse
Annual rept. 1 Jul 2014-30 Jun 2015
VIRGINIA COMMONWEALTH UNIV RICHMOND
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Studies relating to the role autophagy in susceptibility to adriamycin ADR in mouse mammary carcinoma MMC cells generated somewhat contradictory outcomes. Whereas pharmacological inhibition of autophagy using chloroquine CQ did not affect cytotoxicity of ADR, knock down of the autophagy gene, ATG5, resulted in the inhibition of ADR-induced apoptosis. These data suggest that the autophagy induced by ADR that is ATG5-regulated may have cytotoxic characteristics. Using ionizing radiation as a positive control for cytoprotective autophagy in MMC, we also found that ADR induces autophagy but fails to drive autophagy to completion. However, ADRinduced tumor dormancy was prolonged by CQ, both in vitro and in vivo. ADR was also found to induce immunogenic apoptosis, as characterized by membrane translocation of calreticulin CRT, irrespective of the blockade of autophagy by CQ. As ADR did not induce autophagy in human SKBR3 tumor cell line, we plan to evaluate the capacity of ADR to promote autophagy in p53 wild-type MCF7 cells and p53 mutant MDA-MB-453 human breast tumor cells. We will also determine whether autophagy may be differentially regulated by select autophagy genes such that e.g. ATG5 is involved in cytotoxic autophagy whereas ATG7 or ATG12 are involved in nonprotective autophagy induced by ADR.
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