ACK1 upregulated the proliferation of head and neck squamous cell carcinoma cells by promoting p27 phosphorylation and degradation

Peng, Hsuan-Hsiang; Yang, Hao-Chin; Rupa, Darius; Yen, Chun-Han; Chiu, Yu‐Han; Yang, Weijia; Luo, Fuh-Jinn; Yuan, Ta‐Chun

doi:10.1007/s12079-022-00670-6

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…p27 degradation is coordinated by phosphorylation (at Ser10, Thr157, Thr187, and Thr198). Several protein kinases including c-Src, Yes, Lyn, Brk, JAK2 and Abl have been reported to orchestrate this phosphorylation [ 66 ]. Typically, such phosphorylation facilitates the recruitment of the E3 ligase Skp2, which triggers p27 ubiquitin-mediated degradation [ 67 ].…”

Section: Ack’s Role In Regulating Protein Stabilitymentioning

confidence: 99%

“…Subsequent knockdown or inhibition of ACK in HNSCC cell lines (OECM-1, HSC-3, and SAS) enhanced p27 levels and inhibited cell proliferation. Further work uncovered the mechanistic details and ACK was shown to phosphorylate p27 at Tyr88, facilitating the canonical interaction with Skp2 and proteasomal degradation ( Figure 2 ) [ 66 ].…”

Section: Ack’s Role In Regulating Protein Stabilitymentioning

confidence: 99%

“…ACK is also known to mediate activation of the serine/threonine kinase AKT (see below), a known mediator of p27 degradation [ 66 , 68 ]. Knockdown of AKT in HSNCC cells stably expressing ACK restored the expression of p27, suggesting that AKT also plays an important role in regulating p27’s stability in HSNCC [ 66 ]. However, further mechanistic interrogation is required to uncover ACK/AKT’s precise role.…”

Section: Ack’s Role In Regulating Protein Stabilitymentioning

confidence: 99%

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ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer

et al. 2023

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Activated Cdc42-associated kinase (ACK), a non-receptor tyrosine kinase, is an effector for the small GTPase Cdc42. ACK is emerging as an important component of the cancer landscape and thus, a promising target for the treatment of many malignancies. ACK is also being increasingly recognized as a potentially influential player in the regulation of protein homoeostasis. The delicate equilibrium between protein synthesis and protein degradation is crucial for healthy cell function and dysregulation of protein homoeostasis is a common occurrence in human disease. Here, we review the molecular mechanisms by which ACK regulates the stability of diverse cellular proteins (e.g. EGFR, p27, p53, p85 isoforms and RhoGDI-3), some of which rely on the kinase activity of ACK while others, interestingly, do not. Ultimately, further research will be required to bridge our knowledge gaps and determine if ACK regulates the stability of further cellular proteins but collectively, such mechanistic interrogation would contribute to determining whether ACK is a promising target for anti-cancer therapy. In therapeutics, proteasome inhibitors are an efficacious but problematic class of drugs. Targeting other modulators of proteostasis, like ACK, could open novel avenues for intervention.

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Section: Ack’s Role In Regulating Protein Stabilitymentioning

confidence: 99%

Section: Ack’s Role In Regulating Protein Stabilitymentioning

confidence: 99%

Section: Ack’s Role In Regulating Protein Stabilitymentioning

confidence: 99%

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ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer

et al. 2023

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ACSL4 upregulates IFI44 and IFI44L expression and promotes the proliferation and invasiveness of head and neck squamous cell carcinoma cells

Rupa,

Chuang,

et al. 2024

Cancer Science

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Reprogramming of cellular energy metabolism, including deregulated lipid metabolism, is a hallmark of head and neck squamous cell carcinoma (HNSCC). However, the underlying molecular mechanisms remain unclear. Long‐chain acyl‐CoA synthetase 4 (ACSL4), which catalyzes fatty acids to form fatty acyl‐CoAs, is critical for synthesizing phospholipids or triglycerides. Despite the differing roles of ACSL4 in cancers, our data showed that ACSL4 was highly expressed in HNSCC tissues, positively correlating with poor survival rates in patients. Knockdown of ACSL4 in HNSCC cells led to reduced cell proliferation and invasiveness. RNA sequencing analyses identified interferon‐induced protein 44 (IFI44) and interferon‐induced protein 44‐like (IFI44L), encoded by two interferon‐stimulated genes, as potential effectors of ACSL4. Silencing IFI44 or IFI44L expression in HNSCC cells decreased cell proliferation and invasiveness. Manipulating ACSL4 expression or activity modulated the expression levels of JAK1, tyrosine kinase 2 (TYK2), signal transducer and activator of transcription 1 (STAT1), interferon α (IFNα), IFNβ, and interferon regulatory factor 1 (IRF1), which regulate IFI44 and IFI44L expression. Knockdown of IRF1 reduced the expression of JAK1, TYK2, IFNα, IFNβ, IFI44, or IFI44L and diminished cell proliferation and invasiveness. Our results suggest that ACSL4 upregulates interferon signaling, enhancing IFI44 and IFI44L expression and promoting HNSCC cell proliferation and invasiveness. Thus, ACSL4 could serve as a novel therapeutic target for HNSCC.

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Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1

Zhu

Cao

Zhao

et al. 2023

Mol Med

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Background Activated Cdc42-associated kinase 1 (ACK1) is a promising druggable target for cancer, but its inhibitors only showed moderate effects in clinical trials. The study aimed to investigate the underlying mechanisms and improve the antitumor efficacy of ACK1 inhibitors. Methods RNA-seq was performed to determine the downstream pathways of ACK. Using Lasso Cox regression analysis, we built a risk signature with ACK1-related autophagy genes in the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) project. The performance of the signature in predicting the tumor immune environment and response to immunotherapy and chemotherapy were assessed in LUAD. CCK8, mRFP-GFP-LC3 assay, western blot, colony formation, wound healing, and transwell migration assays were conducted to evaluate the effects of the ACK1 inhibitor on lung cancer cells. A subcutaneous NSCLC xenograft model was used for in vivo study. Results RNA-seq revealed the regulatory role of ACK1 in autophagy. Furthermore, the risk signature separated LUAD patients into low- and high-risk groups with significantly different prognoses. The two groups displayed different tumor immune environments regarding 28 immune cell subsets. The low-risk groups showed high immune scores, high CTLA4 expression levels, high immunophenoscore, and low DNA mismatch repair capacity, suggesting a better response to immunotherapy. This signature also predicted sensitivity to commonly used chemotherapy and targeted drugs. In vitro, the ACK1 inhibitors (AIM-100 and Dasatinib) appeared to trigger adaptive autophagy-like response to protect lung cancer cells from apoptosis and activated the AMPK/mTOR signaling pathway, partially explaining its moderate antitumor efficacy. However, blocking lysosomal degradation with chloroquine/Bafilamycine A1 or inhibiting AMPK signaling with compound C/shPRKAA1 enhanced the ACK1 inhibitor’s cytotoxic effects on lung cancer cells. The efficacy of the combined therapy was also verified using a mouse xenograft model. Conclusions The resulting signature from ACK1-related autophagy genes robustly predicted survival and drug sensitivity in LUAD. The lysosomal degradation inhibition improved the therapeutic effects of the ACK1 inhibitor, suggesting a potential role for autophagy in therapy evasion.

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ACK1 upregulated the proliferation of head and neck squamous cell carcinoma cells by promoting p27 phosphorylation and degradation

Cited by 4 publications

References 36 publications

ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer

ACKnowledging the role of the Activated-Cdc42 associated kinase (ACK) in regulating protein stability in cancer

ACSL4 upregulates IFI44 and IFI44L expression and promotes the proliferation and invasiveness of head and neck squamous cell carcinoma cells

Improvement of ACK1-targeted therapy efficacy in lung adenocarcinoma using chloroquine or bafilomycin A1

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