Targeting PRPK and TOPK for skin cancer prevention and therapy

Roh, Eunmiri; Lee, Mee-Hyun; Zykova, Tatyana A.; Zhu, Feng; Nadas, Janos; Kim, Hong Gyum; Bae, Ki Beom; Li, Yan; Cho, Yong‐Yeon; Curiel‐Lewandrowski, Clara; Einspahr, Janine G.; Dickinson, Sally E.; Bode, Ann M.; Dong, Zigang

doi:10.1038/s41388-018-0350-9

Cited by 28 publications

(37 citation statements)

References 55 publications

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“…Through this mechanism, manipulation of TOPK expression in HCT116 colon cancer xenografts is sufficient to influence migration and metastatic growth in mouse liver tissue 29 . Relative expression of TOPK and its downstream target, PRPK, are also related to metastatic potential in colorectal carcinoma and squamous cell carcinoma 30 , 31 . Further, TOPK knockout mice are resistant to solar stimulated light-induced skin cancer 31 .…”

Section: Preclinical Rationale: Topk Overexpression In Cancermentioning

confidence: 99%

“…Relative expression of TOPK and its downstream target, PRPK, are also related to metastatic potential in colorectal carcinoma and squamous cell carcinoma 30 , 31 . Further, TOPK knockout mice are resistant to solar stimulated light-induced skin cancer 31 . For patients with acute myeloid leukaemia (AML), myeloid maturation in FTL3 -ITD positive AML cells appears to be partially suppressed by a feedback loop between TOPK and the transcription factor responsible for granulocyte differentiation, CEBPA.…”

Section: Preclinical Rationale: Topk Overexpression In Cancermentioning

confidence: 99%

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T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics

et al. 2018

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‘Targeted’ or ‘biological’ cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.

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Section: Preclinical Rationale: Topk Overexpression In Cancermentioning

confidence: 99%

Section: Preclinical Rationale: Topk Overexpression In Cancermentioning

confidence: 99%

T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics

et al. 2018

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“…Elevated expression of TOPK is associated with poor prognosis of ovarian cancer (Ikeda et al, 2016), oesophageal squamous carcinoma (Ohashi et al, 2016), and gastric carcinoma patients (Ohashi et al, 2017). TOPK directly phosphorylates ERK, histone H3 (Ser10), histone H2AX (Ser139), peroxiredoxin 1 (PRX1, Ser32), JNK1 (Thr183/Tyr185), and p53‐related protein kinase (PRPK, Ser250; Oh et al, 2007; Roh et al, 2018; Zykova et al, 2010). These phosphorylated substrates of TOPK activate down‐stream signalling cascades, including the MAPKs, and ribosomal S‐6 kinase (RSK), and transcription factors, including activator protein‐1 (AP‐1) or NF‐κB, thereby promoting cell proliferation, migration, and invasion (Aksamitiene et al, 2010; Oh et al, 2007; Park et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Acetylshikonin suppressed growth of colorectal tumour tissue and cells by inhibiting the intracellular kinase, T‐lymphokine‐activated killer cell‐originated protein kinase.

Zhao

Choi

Wei

et al. 2020

British J Pharmacology

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Background and Purpose: Overexpression or aberrant activation of the T-lymphokine-activated killer cell-originated protein kinase (TOPK) promotes gene expression and growth of solid tumours, implying that TOPK would be a rational target in developing novel anticancer drugs. Acetylshikonin, a diterpenoid compound isolated from Lithospermum erythrorhizon root, exerts a range of biological activities. Here we have investigated whether acetylshikonin, by acting as an inhibitor of TOPK, can attenuate the proliferation of colorectal cancer cells and the growth of patient-derived tumours, in vitro and in vivo. Experimental Approach: Targets of acetylshikonin, were identified using kinase profiling analysis, kinetic/binding assay, and computational docking analysis and knockdown techniques. Effects of acetylshikonin on colorectal cancer growth and the underlying mechanisms were evaluated in cell proliferation assays, propidium iodide and annexin-V staining analyses and western blots. Patient-derived tumour xenografts in mice (PDX) and immunohistochemistry were used to assess anti-tumour effects of acetylshikonin. Key Results: Acetylshikonin directly inhibited TOPK activity, interacting with the ATP-binding pocket of TOPK. Acetylshikonin suppressed cell proliferation by inducing cell cycle arrest at the G1 phase, stimulated apoptosis, and increased the expression of apoptotic biomarkers in colorectal cancer cell lines. Mechanistically, Abbreviations: PDX, patient-derived tumour xenograft; RSK, ribosomal s6 kinase; TOPK, T (T-LAK)-cell-originated protein kinase.Ran Zhao, Bu Young Choi, Lixiao Wei, and Mangaladoss Fredimoses equally contributed in this study.

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“…Recent research results indicated that the levels of phosphorylated TOPK (Thr9) and phosphorylated PRPK (Ser250) are overexpressed in human AKs and SCCs [ 29 ]. Furthermore, knocking out the TOPK expression completely blocked the SSL-induced SCC development in SKH-1 hairless mice [ 29 ]. Moreover, the results suggested that PRPK is a novel molecular driver associated with the TOPK pathway in skin carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

Are FDA-Approved Sunscreen Components Effective in Preventing Solar UV-Induced Skin Cancer?

Bode

Roh

2020

Cells

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Solar ultraviolet (SUV) exposure is a major risk factor in the etiology of cutaneous squamous cell carcinoma (cSCC). People commonly use sunscreens to prevent SUV-induced skin damage and cancer. Nonetheless, the prevalence of cSCC continues to increase every year, suggesting that commercially available sunscreens might not be used appropriately or are not completely effective. In the current study, a solar simulated light (SSL)-induced cSCC mouse model was used to investigate the efficacy of eight commonly used FDA-approved sunscreen components against skin carcinogenesis. First, we tested FDA-approved sunscreen components for their ability to block UVA or UVB irradiation by using VITRO-SKIN (a model that mimics human skin properties), and then the efficacy of FDA-approved sunscreen components was investigated in an SSL-induced cSCC mouse model. Our results identified which FDA-approved sunscreen components or combinations are effective in preventing cSCC development. Not surprisingly, the results indicated that sunscreen combinations that block both UVA and UVB significantly suppressed the formation of cutaneous papillomas and cSCC development and decreased the activation of oncoproteins and the expression of COX-2, keratin 17, and EGFR in SSL-exposed SKH-1 (Crl:SKH1-Hrhr) hairless mouse skin. Notably, several sunscreen components that were individually purported to block both UVA and UVB were ineffective alone. At least one component had toxic effects that led to a high mortality rate in mice exposed to SSL. Our findings provide new insights into the development of the best sunscreen to prevent chronic SUV-induced cSCC development.

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Targeting PRPK and TOPK for skin cancer prevention and therapy

Cited by 28 publications

References 55 publications

T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics

T-LAK cell-originated protein kinase (TOPK): an emerging target for cancer-specific therapeutics

Acetylshikonin suppressed growth of colorectal tumour tissue and cells by inhibiting the intracellular kinase, T‐lymphokine‐activated killer cell‐originated protein kinase.

Are FDA-Approved Sunscreen Components Effective in Preventing Solar UV-Induced Skin Cancer?

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