Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway.
Sunitinib treatment promotes metastasis of drug-resistant renal cell carcinoma via TFE3 signaling pathway.
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DOI：
10.1038/s41419-021-03511-3
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发表时间：
2021-02-26
影响因子：
9
通讯作者：
Fan Y
中科院分区：
文献类型：
--
作者：
Li L;Zhao S;Liu Z;Zhang N;Pang S;Liu J;Liu C;Fan Y
受体酪氨酸激酶（RTK）抑制剂，如舒尼替尼和索拉非尼，仍然是治疗mRCC的一线药物。获得性耐药和转移是治疗失败的主要原因。然而，在对舒尼替尼表现出良好反应的转移性肾细胞癌（mRCC）的情况下，我们发现长期使用舒尼替尼治疗可促进溶酶体生物合成和胞吐作用，从而触发RCC的转移。通过构建体内舒尼替尼耐药细胞系，我们证实了TFE 3在RCC对舒尼替尼的获得性耐药中起关键作用。在舒尼替尼的刺激下，TFE 3继续进入细胞核，促进内质网（ER）蛋白E-Syt 1的表达。E-Syt 1和溶酶体膜蛋白Syt 7形成异二聚体，其诱导ER片段化、Ca 2+释放和溶酶体胞吐作用。溶酶体胞吐作用具有两个功能：将舒尼替尼从细胞质中泵出，促进肾癌对舒尼替尼的耐药;将组织蛋白酶B（CTSB）释放到细胞外基质（ECM）中，降解ECM，增强肾癌的侵袭和转移能力。我们的研究发现，虽然舒尼替尼是治疗mRCC的有效药物，但一旦RCC对舒尼替尼产生耐药，舒尼替尼治疗会促进转移。
Receptor tyrosine kinase (RTK) inhibitors, such as sunitinib and sorafenib, remain the first-line drugs for the treatment of mRCC. Acquired drug resistance and metastasis are the main causes of treatment failure. However, in the case of metastasis Renal Cell Cancer (mRCC), which showed a good response to sunitinib, we found that long-term treatment with sunitinib could promote lysosome biosynthesis and exocytosis, thereby triggering the metastasis of RCC. By constructing sunitinib-resistant cell lines in vivo, we confirmed that TFE3 plays a key role in the acquired resistance to sunitinib in RCC. Under the stimulation of sunitinib, TFE3 continued to enter the nucleus, promoting the expression of endoplasmic reticulum (ER) protein E-Syt1. E-Syt1 and the lysosomal membrane protein Syt7 form a heterodimer, which induces ER fragmentation, Ca2+ release, and lysosomal exocytosis. Lysosomal exocytosis has two functions: pumping sunitinib out from the cytoplasm, which promotes resistance to sunitinib in RCC, releasing cathepsin B (CTSB) into the extracellular matrix (ECM), which can degrade the ECM to enhance the invasion and metastasis ability of RCC. Our study found that although sunitinib is an effective drug for the treatment of mRCC, once RCC has acquired resistance to sunitinib, sunitinib treatment will promote metastasis.
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DOI：
10.1038/nrurol.2010.47
发表时间：
2010-05
期刊：
Nature reviews. Urology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.5
作者：
Giordano F;Saheki Y;Idevall-Hagren O;Colombo SF;Pirruccello M;Milosevic I;Gracheva EO;Bagriantsev SN;Borgese N;De Camilli P
通讯作者：
De Camilli P
影响因子：
11.4
作者：
Nascimbeni, Anna Chiara;Giordano, Francesca;Morel, Etienne
通讯作者：
Morel, Etienne
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
50.3
作者：
Cooke VG;LeBleu VS;Keskin D;Khan Z;O'Connell JT;Teng Y;Duncan MB;Xie L;Maeda G;Vong S;Sugimoto H;Rocha RM;Damascena A;Brentani RR;Kalluri R
通讯作者：
Kalluri R