A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma
Xiaochao Tan, … , Chad J. Creighton, Jonathan M. Kurie
Xiaochao Tan, … , Chad J. Creighton, Jonathan M. Kurie
Published September 15, 2020
Citation Information: J Clin Invest. 2021;131(1):e137186. https://doi.org/10.1172/JCI137186.
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Research Article Cell biology Oncology

A protumorigenic secretory pathway activated by p53 deficiency in lung adenocarcinoma

Abstract

Therapeutic strategies designed to target TP53-deficient cancer cells remain elusive. Here, we showed that TP53 loss initiated a pharmacologically actionable secretory process that drove lung adenocarcinoma (LUAD) progression. Molecular, biochemical, and cell biological studies showed that TP53 loss increased the expression of Golgi reassembly and stacking protein 55 kDa (G55), a Golgi stacking protein that maintains Golgi organelle integrity and is part of a GOLGIN45 (G45)–myosin IIA–containing protein complex that activates secretory vesicle biogenesis in the Golgi. TP53 loss activated G55-dependent secretion by relieving G55 and myosin IIA from miR-34a–dependent silencing. G55-dependent secreted proteins enhanced the proliferative and invasive activities of TP53-deficient LUAD cells and promoted angiogenesis and CD8+ T cell exhaustion in the tumor microenvironment. A small molecule that blocks G55-G45 interactions impaired secretion and reduced TP53-deficient LUAD growth and metastasis. These results identified a targetable secretory vulnerability in TP53-deficient LUAD cells.

Authors

Xiaochao Tan, Lei Shi, Priyam Banerjee, Xin Liu, Hou-Fu Guo, Jiang Yu, Neus Bota-Rabassedas, B. Leticia Rodriguez, Don L. Gibbons, William K. Russell, Chad J. Creighton, Jonathan M. Kurie

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Figure 3

G55 activates the secretion of protumorigenic effector proteins.

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G55 activates the secretion of protumorigenic effector proteins. (A) Inv...
(A) Invasion assays of H1299 cells in Boyden chambers performed after 24 hours of treatment with conditioned medium (CM) from G55-deficient or G55-replete cells. (B) Anchorage-dependent colony formation assays performed on G55-deficient (shG55) or G55-replete (shCTL) H2122 cells after treatment for 10 days with or without (–) CM from G55-deficient or G55-replete cells. (C) Volcano plot of proteins identified by LC-MS analysis of CM collected from H1299 cells (shG55 or shCTL). Proteins (dots) plotted by P value (y axis) and fold change (x axis). Fold change = 1.4, P = 0.05 indicated (vertical and horizontal dotted lines, respectively). Proteins of interest are labeled. (D) WB analysis of CM samples. Mean densitometric values of triplicate CM samples relative to control (siCTL) (bar graph). (E and F) Anchorage-independent colony formation (E) and cell migration and invasion (F) assays. Results expressed relative to control (siCTL). (G) Orthotopic lung tumor size and contralateral lung metastasis numbers at necropsy 5 weeks after injecting 1 × 106 tumor cells. (H–J) WB analysis of triplicate CM samples from parental and TP53-KO A549 cells (H) or H1299 cells subjected to ectopic expression of p53 (I) or miR-34a (J). Densitometric values relative to controls (bar graphs). Values are mean ± SD. n = 3, unless otherwise indicated. P values: ANOVA (A, B, and D–G), 2-sided t test (all others).