Tibetan Traditional Medical College, Lhasa, China.
Yantai Mountain Hospital, Yantai, Shandong, China.
PLoS One. 2023 Mar 13;18(3):e0281577. doi: 10.1371/journal.pone.0281577. eCollection 2023.
Evidence shows that chaperone-mediated autophagy (CMA) is involved in cancer cell pathogenesis and progression. However, the potential role of CMA in breast cancer angiogenesis remains unknown. We first manipulated CMA activity by knockdown and overexpressing of lysosome-associated membrane protein type 2A (LAMP2A) in MDA-MB-231, MDA-MB-436, T47D and MCF7 cells. We found that the tube formation, migration and proliferation abilities of human umbilical vein endothelial cells (HUVECs) were inhibited after cocultured with tumor-conditioned medium from breast cancer cells of LAMP2A knockdown. While the above changes were promoted after cocultured with tumor-conditioned medium from breast cancer cells of LAMP2A overexpression. Moreover, we found that CMA could promote VEGFA expression in breast cancer cells and in xenograft model through upregulating lactate production. Finally, we found that lactate regulation in breast cancer cells is hexokinase 2 (HK2) dependent, and knockdown of HK2 can significantly reduce the ability of CMA-mediated tube formation capacity of HUVECs. Collectively, these results indicate that CMA could promote breast cancer angiogenesis via regulation of HK2-dependent aerobic glycolysis, which may serve as an attractive target for breast cancer therapies.
证据表明，伴侣蛋白介导的自噬（CMA）参与了癌细胞的发病机制和进展。然而，CMA 在乳腺癌血管生成中的潜在作用尚不清楚。我们首先通过敲低和过表达溶酶体相关膜蛋白 2A（LAMP2A）来操纵 MDA-MB-231、MDA-MB-436、T47D 和 MCF7 细胞中的 CMA 活性。我们发现，与 LAMP2A 敲低的乳腺癌细胞的肿瘤条件培养基共培养后，人脐静脉内皮细胞（HUVEC）的管形成、迁移和增殖能力受到抑制。而与 LAMP2A 过表达的乳腺癌细胞的肿瘤条件培养基共培养后，上述变化得到促进。此外，我们发现 CMA 可以通过上调乳酸产生来促进乳腺癌细胞和异种移植模型中 VEGFA 的表达。最后，我们发现乳腺癌细胞中的乳酸调节依赖于己糖激酶 2（HK2），敲低 HK2 可以显著降低 CMA 介导的 HUVEC 管形成能力。总之，这些结果表明，CMA 可以通过调节 HK2 依赖性有氧糖酵解来促进乳腺癌血管生成，这可能成为乳腺癌治疗的一个有吸引力的靶点。
