Department of Physiology, Institute of Basic Medical Sciences, School of Basic Medicine Peking Union Medical College, Chinese Academy of Medical Sciences, 5 Dong Dan San Tiao, Beijing, China.
Division of Nephrology, Department of Medicine, Washington University School of Medicine, 660S. Euclid Ave., St. Louis, MO, USA.
Cell Death Dis. 2021 Mar 17;12(4):286. doi: 10.1038/s41419-021-03555-5.
p97/VCP, an evolutionarily concerned ATPase, partakes in multiple cellular proteostatic processes, including the endoplasmic reticulum (ER)-associated protein degradation (ERAD). Elevated expression of p97 is common in many cancers and is often associated with poor survival. Here we report that the levels of p97 positively correlated with the histological grade, tumor size, and lymph node metastasis in breast cancers. We further examined p97 expression in the stem-like cancer cells or cancer stem cells (CSCs), a cell population that purportedly underscores cancer initiation, therapeutic resistance, and recurrence. We found that p97 was consistently at a higher level in the CD44/CD24, ALDH, or PKH26 CSC populations than the respective non-CSC populations in human breast cancer tissues and cancer cell lines and p97 expression also positively correlated with that of SOX2, another CSC marker. To assess the role of p97 in breast cancers, cancer proliferation, mammosphere, and orthotopic growth were analyzed. Similarly as p97 depletion, two pharmacological inhibitors, which targets the ER-associated p97 or globally inhibits p97's ATPase activity, markedly reduced cancer growth and the CSC population. Importantly, depletion or inhibition of p97 greatly suppressed the proliferation of the ALDH CSCs and the CSC-enriched mammospheres, while exhibiting much less or insignificant inhibitory effects on the non-CSC cancer cells. Comparable phenotypes produced by blocking ERAD suggest that ER proteostasis is essential for the CSC integrity. Loss of p97 gravely activated the unfolded protein response (UPR) and modulated the expression of multiple stemness and pluripotency regulators, including C/EBPδ, c-MYC, SOX2, and SKP2, which collectively contributed to the demise of CSCs. In summary, p97 controls the breast CSC integrity through multiple targets, many of which directly affect cancer stemness and are induced by UPR activation. Our findings highlight the importance of p97 and ER proteostasis in CSC biology and anticancer therapy.
p97/VCP 是一种进化上相关的 ATP 酶，参与多种细胞蛋白稳态过程，包括内质网（ER）相关蛋白降解（ERAD）。p97 的高表达在许多癌症中很常见，并且常常与不良预后相关。在这里，我们报告 p97 的水平与乳腺癌的组织学分级、肿瘤大小和淋巴结转移呈正相关。我们进一步研究了 p97 在乳腺癌组织和癌细胞系中的干性肿瘤细胞或癌症干细胞（CSCs）中的表达，CSCs 据称是癌症起始、治疗抵抗和复发的关键。我们发现，p97 在 CD44/CD24、ALDH 或 PKH26 CSC 群体中的水平始终高于相应的非 CSC 群体，p97 的表达也与另一个 CSC 标志物 SOX2 呈正相关。为了评估 p97 在乳腺癌中的作用，我们分析了癌症增殖、类器官和原位生长。与 p97 耗竭类似，两种靶向 ER 相关 p97 或全局抑制 p97 的 ATP 酶活性的药理学抑制剂显著降低了癌症生长和 CSC 群体。重要的是，p97 的耗竭或抑制极大地抑制了 ALDH CSCs 和富含 CSC 的类器官的增殖，而对非 CSC 癌细胞的抑制作用较小或不显著。阻断 ERAD 产生的类似表型表明 ER 蛋白稳态对于 CSC 的完整性是必要的。p97 的缺失严重激活了未折叠蛋白反应（UPR），并调节了多个干性和多能性调节剂的表达，包括 C/EBPδ、c-MYC、SOX2 和 SKP2，它们共同导致 CSCs 的死亡。总之，p97 通过多种靶点控制乳腺癌 CSC 的完整性，其中许多靶点直接影响癌症干性，并被 UPR 激活所诱导。我们的研究结果强调了 p97 和 ER 蛋白稳态在 CSC 生物学和抗癌治疗中的重要性。
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