Atg7 cooperates with Pten loss to drive prostate cancer tumor growth.
Atg7 cooperates with Pten loss to drive prostate cancer tumor growth.
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DOI：
10.1101/gad.274134.115
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发表时间：
2016-02-15
影响因子：
10.5
通讯作者：
DiPaola RS
中科院分区：
文献类型：
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作者：
Santanam U;Banach-Petrosky W;Abate-Shen C;Shen MM;White E;DiPaola RS
为了评估自噬在前列腺癌中的重要性，Santanam等人建立了一种新的本土基因工程小鼠模型，该模型具有可诱导的前列腺特异性Pten肿瘤抑制因子和自噬相关-7 （Atg7）基因缺陷。Atg7缺乏在castrate-naïve和去势抵抗性癌症中产生自噬缺陷表型和延迟pten缺陷前列腺肿瘤进展。了解去势敏感和更具侵袭性去势抵抗性前列腺癌的新治疗范例对于改善临床结果至关重要。作为一个至关重要的细胞过程，自噬通过循环细胞内成分来促进应激耐受性，维持对肿瘤生存至关重要的代谢。为了评估自噬在前列腺癌中的重要性，我们建立了一种新的自体基因工程小鼠模型（GEMM），该模型具有可诱导的前列腺特异性Pten肿瘤抑制因子和自噬相关-7 （Atg7）基因缺失。Atg7缺乏在castrate-naïve和去势抵抗性癌症中产生自噬缺陷表型和延迟pten缺陷前列腺肿瘤进展。atg7缺陷肿瘤显示内质网（ER）应激的证据，表明自噬可能通过管理蛋白质稳态来促进前列腺肿瘤的发生。综上所述，这些数据支持了自噬在新开发的GEMM中castrate-naïve和去势抵抗生长的重要性，为研究抑制自噬的方法与已知和新的治疗晚期前列腺癌的方法提供了新的范式和模型。
To assess the importance of autophagy in prostate cancer, Santanam et al. generated a new autochthonous genetically engineered mouse model with inducible prostate-specific deficiency in the Pten tumor suppressor and autophagy-related-7 (Atg7) gene. Atg7 deficiency produced an autophagy-deficient phenotype and delayed Pten-deficient prostate tumor progression in both castrate-naïve and castrate-resistant cancers. Understanding new therapeutic paradigms for both castrate-sensitive and more aggressive castrate-resistant prostate cancer is essential to improve clinical outcomes. As a critically important cellular process, autophagy promotes stress tolerance by recycling intracellular components to sustain metabolism important for tumor survival. To assess the importance of autophagy in prostate cancer, we generated a new autochthonous genetically engineered mouse model (GEMM) with inducible prostate-specific deficiency in the Pten tumor suppressor and autophagy-related-7 (Atg7) genes. Atg7 deficiency produced an autophagy-deficient phenotype and delayed Pten-deficient prostate tumor progression in both castrate-naïve and castrate-resistant cancers. Atg7-deficient tumors display evidence of endoplasmic reticulum (ER) stress, suggesting that autophagy may promote prostate tumorigenesis through management of protein homeostasis. Taken together, these data support the importance of autophagy for both castrate-naïve and castrate-resistant growth in a newly developed GEMM, suggesting a new paradigm and model to study approaches to inhibit autophagy in combination with known and new therapies for advanced prostate cancer.