Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer

Phelps-Polirer, Kendall; Abt, Melissa; Smith, Danzell; Yeh, Elizabeth S.

doi:10.1371/journal.pone.0153025

Cited by 17 publications

(35 citation statements)

References 38 publications

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“…In GC, the pivotal role of HER2 metastasis has been shown[6,29], but not much is known about the downstream effectors in this process. Although most studies have implicated AKT and ERK as promising therapeutic targets for HER2-positive tumors[27,28,30], JNK, especially in breast cancer, is now emerging as an important molecule in HER2 signaling pathways[11,12]. In the present study, we found positive associations between HER2, JNK and AKT in terms of GC metastasis.…”

Section: Discussionsupporting

confidence: 48%

“…In general, JNK has been established as a key kinase in cancer cell apoptosis[10]. Recently, the role of JNK in HER2 signaling pathway has gained much attention, because JNK activation plays a critical role in the lapatinib-resistance in HER2-positve breast cancer cells[11,12]. However, regarding GC, the biological significance of JNK in relation to HER2 signaling has not been reported.…”

Section: Introductionmentioning

confidence: 99%

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HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer

Choi¹,

Ko²,

Park³

et al. 2016

WJG

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AIMTo investigated the relationships between HER2, c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) with respect to metastatic potential of HER2-positive gastric cancer (GC) cells.METHODSImmunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were used in cell culture experiments.RESULTSIn GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.CONCLUSIONHER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.

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Section: Discussionsupporting

confidence: 48%

Section: Introductionmentioning

confidence: 99%

HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer

Choi¹,

Ko²,

Park³

et al. 2016

WJG

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“…It is currently unknown if EGFR can independently regulate Hunk or if this effect on Hunk expression is due to the dimerization between HER2/ErbB2 and EGFR. Most recently, it has been reported that Hunk knockdown is able to inhibit EGFR activity indicated by reduced EGFR phosphorylation in HER2 + /ErbB2 + breast cancer cells resistant to HER2/ErbB2 inhibitors [25], which could suggest that Hunk participates in a positive feedback loop to regulate EGFR activation.…”

Section: Intracellular Functions Of Hunkmentioning

confidence: 99%

“…Multiple lines of investigation demonstrated that targeting Hunk, either by shRNA knockdown in MMTV- neu -derived mammary tumor cells and HER2 + /ErbB2 + breast cancer cells, or through the use of MMTV- neu -genetically engineered mouse models bred into a Hunk −/− background, significantly impaired tumor growth [13, 24, 25]. It was also reported that a kinase-dead mutant of Hunk impaired tumor growth [24], suggesting Hunk kinase activity is important for the promotion of HER2 + /ErbB2 + mammary tumorigenesis in vivo.…”

Section: Hunk Is Implicated In Her2+/erbb2+ Breast Cancer and Devementioning

confidence: 99%

“…Two recent studies demonstrated that targeting Hunk with shRNA in a HER2 + /ErbB2 + breast cancer cell line derived from a patient who was resistant to trastuzumab impaired mammary tumor growth in vivo [13, 25]. These studies provided evidence to suggest that Hunk regulates the catabolic process of autophagy, which can lead breast cancer cells to become resistant to targeted inhibitors, and that downregulating Hunk by shRNA inhibits autophagy in both primary and drug resistant HER2 + /ErbB2 + breast cancer cells.…”

Section: Hunk Is Implicated In Her2+/erbb2+ Breast Cancer and Devementioning

confidence: 99%

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Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression

Zambrano

Neely

Yeh

2017

Pharmacological Research

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Hormonally Up-regulated Neu-associated Kinase (Hunk) is a protein kinase that was originally identified in the murine mammary gland and has been shown to be highly expressed in Human Epidermal Growth Factor Receptor 2 positive (HER2+/ErbB2+) breast cancer cell lines as well as MMTV-neu derived mammary tumor cell lines. However, the physiological role of Hunk has been largely elusive since its identification. Though Hunk is predicted to be a Serine/Threonine (Ser/Thr) protein kinase with homology to the SNF1/AMPK family of protein kinases, there are no known Hunk substrates that have been identified to date. Recent work demonstrates a role for Hunk in HER2+/ErbB2+ breast cancer progression, including drug resistance to HER2/ErbB2 inhibitors, with Hunk potentially acting downstream of HER2/ErbB2 and the PI3K/Akt pathway. These studies have collectively shown that Hunk plays a vital role in promoting mammary tumorigenesis, as Hunk knockdown via shRNA in xenograft tumor models or crossing MMTV-neu or Pten-deficient genetically engineered mouse models into a Hunk knockout (Hunk−/−) background impairs mammary tumor growth in vivo. Because the majority of HER2+/ErbB2+ breast cancer patients acquire drug resistance to HER2/ErbB2 inhibitors, the characterization of novel drug targets like Hunk that have the potential to simultaneously suppress tumorigenesis and potentially enhance efficacy of current therapeutics is an important facet of drug development. Therefore, work aimed at uncovering specific regulatory functions for Hunk that could contribute to this protein kinase’s role in both tumorigenesis and drug resistance will be informative. This review focuses on what is currently known about this under-studied protein kinase, and how targeting Hunk may prove to be a potential therapeutic target for the treatment of breast cancer.

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Synthesis, Characterization, In‐Vitro and In‐Vivo Anti‐Cancer Evaluation of Novel Benzopyrylium Salts on Colorectal Cancer Model of Drosophila Melanogaster

Rai,

Kumar,

Singh

et al. 2024

ChemistrySelect

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A total of 10 benzopyrylium salts, 7 being novel, were synthesized by Claisen‐Schmidt condensation reaction and characterized by 1H and 13C NMR, High‐Resolution Mass Spectrometry, FT‐IR, and UV‐Vis spectroscopy. The purity of these synthesized compounds was determined by HPLC. The in‐vitro anti‐cancer evaluation of these synthesized benzopyrylium salts was done at National Cancer Institute (NCI), USA, against 60 human cancer cell lines. The compounds 4 and 8 showed promising anti‐cancer activities against various human cancer cell lines. The docking studies of the compounds were carried out against the oncogenic target JNK and their docking scores were compared to that of the known JNK inhibitor SP600125 (Pyrazolanthrone). Compound 4 exhibited an outstanding docking score of −9.0 kcal/mol, comparable to the docking score of SP600125 (−9.3 kcal/mol). The ex‐vivo studies in the hind‐gut of Drosophila were carried out and the inhibitory activity of compound 4 supported the findings of the docking studies. Furthermore, the potent compounds 4 and 8 were taken up for their in‐vivo anti‐cancer evaluation in the colorectal cancer model (CRC) of Drosophila melanogaster. The toxicity studies of these potent compounds were carried out both in wild type and mutant type Drosophila and the lethal doses were determined to be 200 μM.

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Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer

Cited by 17 publications

References 38 publications

HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer

HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer

Hormonally up-regulated neu-associated kinase: A novel target for breast cancer progression

Synthesis, Characterization, In‐Vitro and In‐Vivo Anti‐Cancer Evaluation of Novel Benzopyrylium Salts on Colorectal Cancer Model of Drosophila Melanogaster

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