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Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma.

ABSTRACT: Osimertinib is a promising approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treating patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations, however, almost all patients develop resistance to Osimertinib eventually limiting the long-term efficacy. Autophagy is a vital cellular recycling process promoting Osimertinib resistance. Identifying accurate and efficient autophagy-regulatory factors is of great significance in reducing Osimertinib resistance. This study identified Cezanne, a member of the ovarian tumor protease (OTU)-deubiquitinating family, as an autophagy regulator. Cezanne was highly expressed in Osimertinib-resistant cells, and Cezanne overexpression promoted Osimertinib resistance, while chloroquine (CQ), an autophagy inhibitor, reverted this process. In the Cezanne-overexpressing cells, autophagy was activated even in the absence of autophagy inducers rapamycin and Earle's Balanced Salt Solution (EBSS). Further study showed that Cezanne stabilized PIK3C3 by deubiquitinating K48-linked ubiquitination at Lysine 322. Surprisingly, as a compensatory mechanism of PI3P generation, PIK3C2A was shown to be upregulated by Cezanne by promoting its transcription in a POLR2A-dependent way. Based on these results, Cezanne also accelerates EGFR recycling which may explain the mechanism mediating Cezanne expression and Osimertinib resistance. In conclusion, this study establishes a new model connecting Cezanne, autophagy, and Osimertinib resistance, opening new avenues to explore the effect of Cezanne and autophagy in LUAD.

SUBMITTER: Wang Y

PROVIDER: S-EPMC10439204 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma.

Wang Yadong Y Li Jiahao J Zheng Haotian H Wang Kai K Ren Xiaoyang X Wang Guanghui G Du Jiajun J

Cell death discovery 20230818 1

Osimertinib is a promising approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treating patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations, however, almost all patients develop resistance to Osimertinib eventually limiting the long-term efficacy. Autophagy is a vital cellular recycling process promoting Osimertinib resistance. Identifying accurate and efficient autophagy-regulatory factors is of great significance in reduc ...[more]

PMID: 37596251

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Project description:The mechanism of RP11-838N2.3 promoting cisplatin resistance in lung adenocarcinoma (LAD) was unclear. The RP11-838N2.3 expression level in cells and LAD tissues was detected by qPCR. We constructed lentivirus-mediated GV303 overexpression and GV248 shRNA vector targeting RP11-838N2.3, then infected A549 and A549/DDP cell and furtherly analyzed cell biology. High-throughput gene chip analysis showed that RP11-838N2.3 was significantly upregulated in A549/DDP (change?fold = 66.056595). The qPCR results showed that the expression level of RP11-838N2.3 in A549/DDP cell was significantly higher than that in A549 cells (P < 0.05), and the expression level of RP11-838N2.3 in LAD tissues was also significantly higher than that in adjacent tissues (P < 0.05). The expression level of RP11-838N2.3 in cisplatin-insensitive LAD tissues was also significantly higher than that in cisplatin-sensitive LAD tissues (P < 0.05). Survival analysis showed that OS (overall survival) and DFS (progression-free survival) of high RP11-838N2.3 expression in the cisplatin-sensitive or cisplatin-insensitive LAD group were lower (P < 0.001 and P < 0.001) than those of low RP11-838N2.3 expression in the cisplatin-sensitive or cisplatin-insensitive LAD group. CCK8 showed that the OD450 value of RP11-838N2.3 overexpression increased significantly at 24?h, 48?h, and 72?h after transfection, while the knockdown of RP11-838N2.3 caused OD450 value at 24?h, 48?h, and 72?h after transfection significantly reduced, under the action of cisplatin that had the same trend (P < 0.05). The cell migration showed that the RP11-838N2.3 overexpression increased significantly migration activity and RP11-838N2.3 knockdown inhibited migration activity at 24?h, 48?h, and 72?h after transfection. The same trend was also observed under the action of cisplatin (P < 0.05). The cell invasion showed that the invasion rate of RP11-838N2.3 overexpression increased significantly, while the invasion rate of RP11-838N2.3 knockdown decreased significantly, and the same trend was observed under the action of cisplatin (P < 0.05). Apoptosis results showed that the apoptosis rate of RP11-838N2.3 overexpressed cells decreased significantly and the apoptosis rate of RP11-838N2.3 knockdown cells increased significantly, and the same trend was also observed under the action of cisplatin (P < 0.05). However, the results of cell cycle showed that there was no significant difference in the proportion of cells in each phase of the cell cycle after RP11-838N2.3 overexpression or knockdown (P > 0.05).RP11-838N2.3 was significantly upregulated in cisplatin-resistant cell and tissues of LAD. RP11-838N2.3 could enhance the proliferation, migration, and invasion and inhibit apoptosis of LAD cisplatin-resistant cell. So RP11-838N2.3 could enhance the cisplatin resistance of LAD cells and was a resistant lncRNA molecule.

Project description:Acquired chemotherapy resistance is one of the main culprits in the relapse of breast cancer. But the underlying mechanism of chemotherapy resistance remains elusive. Here, we demonstrate that a small adaptor protein, SH3BGRL, is not only elevated in the majority of breast cancer patients but also has relevance with the relapse and poor prognosis of breast cancer patients. Functionally, SH3BGRL upregulation enhances the chemoresistance of breast cancer cells to the first-line doxorubicin treatment through macroautophagic/autophagic protection. Mechanistically, SH3BGRL can unexpectedly bind to ribosomal subunits to enhance PIK3C3 translation efficiency and sustain ATG12 stability. Therefore, inhibition of autophagy or silence of PIK3C3 or ATG12 can effectively block the driving effect of SH3BGRL on doxorubicin resistance of breast cancer cells in vitro and in vivo. We also validate that SH3BGRL expression is positively correlated with that of PIK3C3 or ATG12, as well as the constitutive occurrence of autophagy in clinical breast cancer tissues. Taken together, our data reveal that SH3BGRL upregulation would be a key driver to the acquired chemotherapy resistance through autophagy enhancement in breast cancer while targeting SH3BGRL could be a potential therapeutic strategy against breast cancer.Abbreviations: ABCs: ATP-binding cassette transporters; Act D: actinomycin D; ACTB/β-actin: actin beta; ATG: autophagy-related; Baf A1: bafilomycin A1; CASP3: caspase 3; CHX: cycloheximide; CQ: chloroquine; Dox: doxorubicin; FBS: fetal bovine serum; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GEO: gene expression omnibus; GFP: green fluorescent protein; G6PD: glucose-6-phosphate dehydrogenase; GSEA: gene set enrichment analysis; IHC: immunochemistry; KEGG: Kyoto Encyclopedia of Genes and Genomes; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; 3-MA: 3-methyladenine; mRNA: messenger RNA; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; SH3BGRL: SH3 domain binding glutamate-rich protein-like; SQSTM1/p62: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.

Dataset Information

Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma.

Publications

Cezanne promoted autophagy through PIK3C3 stabilization and PIK3C2A transcription in lung adenocarcinoma.

Similar Datasets

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