ASAP1 activates the IQGAP1/CDC42 pathway to promote tumor progression and chemotherapy resistance in gastric cancer

Xie, Wangkai; Zheng, Han; Zuo, Ziyi; Xin, Dong; Chen, Hua; Huang, Juanjuan; Zhu, Siyu; Lou, Han; Yu, Zhiqiang; Chen, Chenbin; Chen, Sian; Hu, Yuanbo; Huang, Jingjing; Zhang, Fabiao; Ni, Zhonglin; Shen, Xian; Xue, Xiangyang; Lin, Kuan‐Yu

doi:10.1038/s41419-023-05648-9

Cited by 10 publications

(4 citation statements)

References 52 publications

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“…These findings agree with our observed reduction in cell proliferation from the MTT-based growth assays (Figure 1 C), and previous literature. 27 Later time points 7, 14 and 21 highlighted GOs related to GTPase-dependent regulation, transcription-related processes and serine/threonine kinase activity (Supplementary Figure S2 C). Given the KRAS-ARF6-downstream role of ASAP1, and regulation by the MAPK pathway, downregulation of GTPase activity is expected.…”

Section: Resultsmentioning

confidence: 99%

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Ghose,

Das,

Urgel-Solas

et al. 2023

Preprint

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SUMMARYMetastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in up to 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC proliferation and metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NFκB, TNFα and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis.GRAPHICAL SUMMARY

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Section: Resultsmentioning

confidence: 99%

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Ghose,

Das,

Urgel-Solas

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Hence, studies have endeavored to explore new cancer treatments by identifying novel GC targets. In our prior research, ASAP1 overexpression was found to be correlated to the poorer overall survival of GC [ 14 , 15 ]. Therefore, we demonstrate that ASAP1 is overexpressed in GC cells compared to GES1 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Junnila et al conducted expression analysis of ASAP1 and other genes in both GC and non-malignant GC tissues using affinity capture-based transcript analysis (TRAC assay), revealing differential expressed of ASAP1 between them [ 13 ]. Previous studies have shown that ASAP1 is significantly overexpressed in GC tissues, and is negatively correlated with disease-free survival time and overall survival time [ 14 , 15 ]. Therefore, further investigation is warranted to explore the potential anti-GC effect of ASAP1 .…”

Section: Introductionmentioning

confidence: 99%

Role of ADP ribosylation factor guanylate kinase 1 in the malignant biological behavior of gastric cancer

Luo,

Zhang,

Yang

et al. 2024

Heliyon

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“…Cell division cycle 42 (CDC42), a key member of the Rho GTPase protein family, plays a role in various cellular functions, including cell proliferation, migration, invasion, and pseudopod formation [ 10 , 11 ]. CDC42 effector proteins (CEPs) are a group of effector proteins downstream of CDC42, comprising five members: CDC42EP1/2/3/4/5 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Cell division cycle 42 effector protein 4 inhibits prostate cancer progression by suppressing ERK signaling pathway

Zhang,

Yu,

Gao

et al. 2023

Biomol Biomed

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Prostate cancer (PCa) is the most common malignancy among men worldwide. The cell division cycle 42 effector protein 4 (CDC42EP4) functions downstream of CDC42, yet its role and molecular mechanisms in PCa remain unexplored. This study aimed to elucidate the role of CDC42EP4 in the progression of PCa and its underlying mechanisms. Bioinformatical analysis indicated that CDC42EP4 expression was significantly lower in PCa tissue compared to normal prostate tissue. Cellular phenotyping analysis suggested that CDC42EP4 markedly inhibited the proliferation, migration, and invasion of PCa cells. Xenograft tumor assays further demonstrated that CDC42EP4 suppressed the growth of PCa cells in vivo. Mechanistically, the study established that CDC42EP4 inhibited the ERK pathway in PCa cells. Additionally, the ERK pathway inhibitor PD0325901 was employed, revealing that PD0325901 significantly nullified the effects of CDC42EP4 on PCa cell proliferation, migration, and invasion. Collectively, our findings demonstrate that CDC42EP4 acts as a critical tumor suppressor gene, inhibiting PCa cell proliferation, migration, and invasion through the ERK pathway, thereby presenting potential targets for PCa therapy.

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ASAP1 activates the IQGAP1/CDC42 pathway to promote tumor progression and chemotherapy resistance in gastric cancer

Cited by 10 publications

References 52 publications

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Adaptation to ARF6-depletion in KRAS-driven PDAC is abolished by targeting TLR2

Role of ADP ribosylation factor guanylate kinase 1 in the malignant biological behavior of gastric cancer

Cell division cycle 42 effector protein 4 inhibits prostate cancer progression by suppressing ERK signaling pathway

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