Laura and Isaac Perlmutter Cancer Center, Department of Radiation Oncology, New York University School of Medicine, New York, NY 10016.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2021 Feb 9;118(6). doi: 10.1073/pnas.2021475118.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is highly refractory to current therapies. We had previously shown that PDAC can utilize its high levels of basal autophagy to support its metabolism and maintain tumor growth. Consistent with the importance of autophagy in PDAC, autophagy inhibition significantly enhances response of PDAC patients to chemotherapy in two randomized clinical trials. However, the specific metabolite(s) that autophagy provides to support PDAC growth is not yet known. In this study, we demonstrate that under nutrient-replete conditions, loss of autophagy in PDAC leads to a relatively restricted impairment of amino acid pools, with cysteine levels showing a significant drop. Additionally, we made the striking discovery that autophagy is critical for the proper membrane localization of the cystine transporter SLC7A11. Mechanistically, autophagy impairment results in the loss of SLC7A11 on the plasma membrane and increases its localization at the lysosome in an mTORC2-dependent manner. Our results demonstrate a critical link between autophagy and cysteine metabolism and provide mechanistic insights into how targeting autophagy can cause metabolic dysregulation in PDAC.
胰腺导管腺癌 (PDAC) 是最致命的癌症之一，对当前的治疗方法高度耐受。我们之前曾表明，PDAC 可以利用其高水平的基础自噬来支持其代谢并维持肿瘤生长。与自噬在 PDAC 中的重要性一致，自噬抑制在两项随机临床试验中显著增强了 PDAC 患者对化疗的反应。然而，自噬提供的支持 PDAC 生长的确切代谢物尚不清楚。在这项研究中，我们证明在营养充足的情况下，PDAC 中的自噬丧失会导致氨基酸池相对受限的损害，其中半胱氨酸水平显著下降。此外，我们惊人地发现自噬对于胱氨酸转运蛋白 SLC7A11 的正确膜定位至关重要。在机制上，自噬缺陷会导致 SLC7A11 在质膜上丢失，并以 mTORC2 依赖的方式增加其在溶酶体中的定位。我们的研究结果表明自噬与半胱氨酸代谢之间存在关键联系，并为靶向自噬如何导致 PDAC 代谢失调提供了机制见解。
