Abstract:Background The development of persistent endoplasmic reticulum (ER) stress is one of the cornerstones of prostate carcinogenesis; however, the mechanism is missing. Also, alcohol is a physiological ER stress inducer, and the link between alcoholism and progression of prostate cancer (PCa) is well documented but not well characterized. According to the canonical model, the mediator of ER stress, ATF6, is cleaved sequentially in the Golgi by S1P and S2P proteases; thereafter, the genes responsible for unfolded p… Show more
“…Immunohistochemical analyses of PCa specimens confirmed the elevated expression and nuclear signal of ATF6α in tumors with higher Gleason scores. These data correlate ATF6α activity with PCa progression, and mirror its tumorigenic role in PCa cells that were also previously described in other PCa model systems 40,41 . In line with this, ATF6α ablation either genetically or chemically resulted in reduced viability and impaired survival in CRPC cells.…”
Section: Discussionsupporting
confidence: 87%
“…These data correlate ATF6α activity with PCa progression, and mirror its tumorigenic role in PCa cells that were also previously described in other PCa model systems. 40,41 In line with this, ATF6α ablation either genetically or chemically resulted in reduced viability and impaired survival in CRPC cells. These cell-based evidence potentiate a prosurvival role of ATF6α in CRPC cells and warrants preclinical evaluation of ATF6α inhibition in the future.…”
Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration‐resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin‐A7 treatment. In addition, combined analyses of human CRPC bulk RNA‐seq and single‐cell RNA‐seq (scRNA‐seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14‐gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.
“…Immunohistochemical analyses of PCa specimens confirmed the elevated expression and nuclear signal of ATF6α in tumors with higher Gleason scores. These data correlate ATF6α activity with PCa progression, and mirror its tumorigenic role in PCa cells that were also previously described in other PCa model systems 40,41 . In line with this, ATF6α ablation either genetically or chemically resulted in reduced viability and impaired survival in CRPC cells.…”
Section: Discussionsupporting
confidence: 87%
“…These data correlate ATF6α activity with PCa progression, and mirror its tumorigenic role in PCa cells that were also previously described in other PCa model systems. 40,41 In line with this, ATF6α ablation either genetically or chemically resulted in reduced viability and impaired survival in CRPC cells. These cell-based evidence potentiate a prosurvival role of ATF6α in CRPC cells and warrants preclinical evaluation of ATF6α inhibition in the future.…”
Stress in the endoplasmic reticulum (ER) may perturb proteostasis and activates the unfolded protein response (UPR). UPR activation is frequently observed in cancer cells and is believed to fuel cancer progression. Here, we report that one of the three UPR sensors, ATF6α, was associated with prostate cancer (PCa) development, while both genetic and pharmacological inhibition of ATF6α impaired the survival of castration‐resistance PCa (CRPC) cells. Transcriptomic analyses identified the molecular pathways deregulated upon ATF6α depletion, and also discovered considerable disparity in global gene expression between ATF6α knockdown and Ceapin‐A7 treatment. In addition, combined analyses of human CRPC bulk RNA‐seq and single‐cell RNA‐seq (scRNA‐seq) public datasets confirmed that CRPC tumors with higher ATF6α activity displayed higher androgen receptor (AR) activity, proliferative and neuroendocrine (NE) like phenotypes, as well as immunosuppressive features. Lastly, we identified a 14‐gene set as ATF6α NE gene signature with encouraging prognostic power. In conclusion, our results indicate that ATF6α is correlated with PCa progression and is functionally relevant to CRPC cell survival. Both specificity and efficacy of ATF6α inhibitors require further refinement and evaluation.
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