Identification of breast cancer cell subtypes sensitive to ATG4B inhibition.
Identification of breast cancer cell subtypes sensitive to ATG4B inhibition.
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DOI：
10.18632/oncotarget.11408
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发表时间：
2016-10-11
期刊：
影响因子：
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通讯作者：
Gorski SM
中科院分区：
文献类型：
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作者：
Bortnik S;Choutka C;Horlings HM;Leung S;Baker JH;Lebovitz C;Dragowska WH;Go NE;Bally MB;Minchinton AI;Gelmon KA;Gorski SM
自噬是一种溶酶体介导的降解和回收过程，在晚期恶性肿瘤中发挥作用，促进癌细胞存活并促进癌症进展和耐药性。虽然正在研究用于癌症治疗的各种自噬抑制策略，但需要制定这些自噬抑制剂相应的患者选择标准。由于其在自噬过程中的核心作用，半胱氨酸蛋白酶 ATG4B 是被视为潜在治疗靶点的自噬蛋白之一。在这项研究中，我们研究了乳腺癌中 ATG4B 的表达，乳腺癌是一种由多种分子亚型组成的异质性疾病。我们检查了一组乳腺癌细胞系、异种移植肿瘤和乳腺癌患者标本中 ATG4B 的蛋白表达，发现 HER2 和 ATG4B 蛋白表达之间呈正相关。我们发现 HER2 阳性细胞（而非 HER2 阴性乳腺癌细胞）需要 ATG4B 在压力下生存。在 HER2 阳性细胞中，在饥饿和 HER2 抑制条件下，细胞保护性自噬均依赖于 ATG4B。在曲妥珠单抗敏感和耐药的 HER2 过表达乳腺癌细胞中，通过 siRNA 联合敲低 ATG4B 和 HER2 会导致细胞活力显着降低，而与单独曲妥珠单抗治疗相比，ATG4B 敲低与曲妥珠单抗的组合会导致细胞活力更大程度的降低。这些结果共同证明了 ATG4B 阳性表达与 HER2 阳性乳腺癌的新关联，并表明该亚型适合新兴的 ATG4B 抑制策略。
Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target. In this study, we investigated the expression of ATG4B in breast cancer, a heterogeneous disease comprised of several molecular subtypes. We examined a panel of breast cancer cell lines, xenograft tumors, and breast cancer patient specimens for the protein expression of ATG4B, and found a positive association between HER2 and ATG4B protein expression. We showed that HER2-positive cells, but not HER2-negative breast cancer cells, require ATG4B to survive under stress. In HER2-positive cells, cytoprotective autophagy was dependent on ATG4B under both starvation and HER2 inhibition conditions. Combined knockdown of ATG4B and HER2 by siRNA resulted in a significant decrease in cell viability, and the combination of ATG4B knockdown with trastuzumab resulted in a greater reduction in cell viability compared to trastuzumab treatment alone, in both trastuzumab-sensitive and -resistant HER2 overexpressing breast cancer cells. Together these results demonstrate a novel association of ATG4B positive expression with HER2 positive breast cancers and indicate that this subtype is suitable for emerging ATG4B inhibition strategies.