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INPP4B 促进乳腺癌中 PI3Kα 依赖性晚期内体的形成和 Wnt/β-连环蛋白信号通路。

INPP4B promotes PI3Kα-dependent late endosome formation and Wnt/β-catenin signaling in breast cancer.

机构信息

Cancer Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia.

出版信息

Nat Commun. 2021 May 25;12(1):3140. doi: 10.1038/s41467-021-23241-6.

DOI:10.1038/s41467-021-23241-6
PMID:34035258
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8149851/
Abstract

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3β lysosomal degradation and activation of Wnt/β-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER breast cancer via PI(3,4)P to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/β-catenin therapies.

摘要

INPP4B 通过将 PI(3,4)P 转化为 PI(3)P 来抑制 PI3K/AKT 信号通路，而 INPP4B 的失活在三阴性乳腺癌中很常见。矛盾的是，INPP4B 也是其他癌症中报道的癌基因。这些相反的 INPP4B 作用如何与 PI3K 调节相关尚不清楚。我们报告说，PIK3CA 突变型 ER 乳腺癌表现出增加的 INPP4B mRNA 和蛋白表达，并且 INPP4B 增加了 PIK3CA 突变型 ER 乳腺癌细胞的增殖和肿瘤生长，尽管 AKT 信号被抑制。我们使用整合蛋白质组学、转录组学和成像技术证明，INPP4B 通过与 Rab7 相互作用定位于晚期内体，从而增加了内体 PI3Kα 依赖性 PI(3,4)P 向 PI(3)P 的转化、晚期内体/溶酶体的数量和货物运输，从而增强了 GSK3β 溶酶体降解和 Wnt/β-catenin 信号的激活。在机制上，Wnt 抑制或 PI(3)P 效应物 Hrs 的耗竭减少了 INPP4B 介导的细胞增殖和肿瘤生长。因此，INPP4B 通过晚期内体上的 PI(3,4)P 向 PI(3)P 的转化，促进 ER 乳腺癌中 PI3Kα 与 Wnt 信号的串扰，表明这些肿瘤可能可以通过联合使用 PI3K 和 Wnt/β-catenin 疗法进行靶向治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/80df4e55bc1b/41467_2021_23241_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/7dc04f3d6c31/41467_2021_23241_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/654ace72b92c/41467_2021_23241_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/c36f6f00a67c/41467_2021_23241_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/f51e0dc70f6d/41467_2021_23241_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/a8612ff00430/41467_2021_23241_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/294aedb6f637/41467_2021_23241_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/80df4e55bc1b/41467_2021_23241_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/7dc04f3d6c31/41467_2021_23241_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/654ace72b92c/41467_2021_23241_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/c36f6f00a67c/41467_2021_23241_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/f51e0dc70f6d/41467_2021_23241_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/a8612ff00430/41467_2021_23241_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/294aedb6f637/41467_2021_23241_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cc8a/8149851/80df4e55bc1b/41467_2021_23241_Fig7_HTML.jpg

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