Abstract
Prostate cancer (PC) is one of the leading causes of death in males. Available treatments often lead to the appearance of chemoresistant foci and metastases, with mechanisms still partially unknown. Within tumour mass, autophagy may promote cell survival by enhancing cancer cells tolerability to different cell stresses, like hypoxia, starvation or those triggered by chemotherapic agents. Because of its connection with the apoptotic pathways, autophagy has been differentially implicated, either as prodeath or prosurvival factor, in the appearance of more aggressive tumours. Here, in three PC cells (LNCaP, PC3, and DU145), we tested how different autophagy inducers modulate docetaxel-induced apoptosis. We selected the mTOR-independent disaccharide trehalose and the mTOR-dependent macrolide lactone rapamycin autophagy inducers. In castration-resistant PC (CRPC) PC3 cells, trehalose specifically prevented intrinsic apoptosis in docetaxel-treated cells. Trehalose reduced the release of cytochrome c triggered by docetaxel and the formation of aberrant mitochondria, possibly by enhancing the turnover of damaged mitochondria via autophagy (mitophagy). In fact, trehalose increased LC3 and p62 expression, LC3-II and p62 (p62 bodies) accumulation and the induction of LC3 puncta. In docetaxel-treated cells, trehalose, but not rapamycin, determined a perinuclear mitochondrial aggregation (mito-aggresomes), and mitochondria specifically colocalized with LC3 and p62-positive autophagosomes. In PC3 cells, rapamycin retained its ability to activate autophagy without evidences of mitophagy even in presence of docetaxel. Interestingly, these results were replicated in LNCaP cells, whereas trehalose and rapamycin did not modify the response to docetaxel in the ATG5-deficient (autophagy resistant) DU145 cells. Therefore, autophagy is involved to alter the response to chemotherapy in combination therapies and the response may be influenced by the different autophagic pathways utilized and by the type of cancer cells.
Highlights
In men, prostate cancer (PC) is the second most common form of cancer and one of the leading causes of cancer death
100 mM of trehalose was selected to activate autophagy[31,42] which was analysed evaluating nuclear translocation of transcription factor EB (TFEB)[43], mRNA expression and protein levels and distribution of two classical autophagy markers: microtubule-associated protein1A/1B-light chain 3 (LC3) and the sequestosome-1 (SQSTM1) or p6244
Since trehalose and rapamycin exert different role on the intrinsic apoptotic pathway triggered by docetaxel, we evaluated whether these autophagy inducers have a different effect on docetaxel-induced cytotoxicity
Summary
Prostate cancer (PC) is the second most common form of cancer and one of the leading causes of cancer death. PC is initially hormone-dependent and androgen deprivation therapy (ADT) is the preferred treatment used for relapsed and metastatic PC patients[1]. During ADT many patients develop metastatic castration-resistant PC (CRPC)[2,3,4], and they are treated with chemotherapeutic agent, like docetaxel[5,6,7] which, Macroautophagy (hereafter autophagy) is a conserved degradative pathway in which proteins or cytoplasmic components are engulfed into autophagosomes that fuse with lysosomes, for their degradation[10]. Autophagy promotes cell survival in response to starvation or other cell stresses. Autophagy has been implicated in the aetiology of cancer, acting as either prodeath or prosurvival factor depending on type and stage of cancer considered.
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