CaM kinase control of AKT and LNCaP cell survival

Schmitt, John; Smith, Samantha F.; Hart, Brendon; Fletcher, Luke B.

doi:10.1002/jcb.24020

Cited by 20 publications

(16 citation statements)

References 62 publications

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“…Inhibition of the chloride channel activity or knockdown of ANO1 decreased EGFR phosphorylation and subsequently inhibited AKT, SRC, and ERK activation. Furthermore, depletion of ANO1 or inhibition of its biochemical activity blocked CAMKII activation, perhaps also contributing to decreased AKT and ERK phosphorylation as reported previously (33,(36)(37)(38). Consistent with these findings, overexpression of ANO1 in an ANO1-negative cell line promoted cell growth and led to the phosphorylation of both EGFR and CAMKII, indicating the activation of both pathways by ANO1 overexpression.…”

Section: Ano1 Regulates Egfr-and Calcium-dependent Signaling Pathwayssupporting

confidence: 88%

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Britschgi

Bill

Brinkhaus

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

269

373

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The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.ion channel | CaCCinh-A01 | TMEM16A | HNSCC | ESCC

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Section: Ano1 Regulates Egfr-and Calcium-dependent Signaling Pathwayssupporting

confidence: 88%

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Britschgi

Bill

Brinkhaus

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

269

373

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“…The role for the different isoforms of CaM Kinases in oncogenesis is rapidly emerging and evidence supports the involvement for CaM KK, CaM KI, CaM KIV, CaM KII as well as their various substrates and cellular targets in cancer development [60,[68][69][70][71][72][73][74]. Consistent with our data, Iglewski et al demonstrated that urotensin treatment of primary smooth muscle cells activated a CaM KK/CaM KI/ERK proliferation pathway although the ability of other hormones to inhibit this process was not examined [75].…”

Section: Discussionsupporting

confidence: 88%

“…To ensure that STO-609 was acting to selectively inhibit CaM KK signaling in our system, MCF-7 cells were also stimulated with EGF in the presence or absence of STO-609. Consistent with other studies [31,56,57,60], STO-609 did not block EGF-dependent stimulation of Elk-1 phosphorylation (Fig. 1d).…”

Section: Statisticssupporting

confidence: 93%

“…Similarly, recent data suggests that inhibiting CaM KK reduced both ERK and AKT activation as well as gastric cancer cell growth [76]. We did not evaluate the role of AKT or AMPK in our system although they may contribute to cell growth and survival downstream of CaM KK in several cancer cell types including breast, prostate, and myeloid [60,70,77,78]. Future studies may examine the specific effect that E2 has on AKT or AMPK activation and weather Vit D impairs their phosphorylation in breast cancer cells.…”

Section: Discussionmentioning

confidence: 96%

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Estrogen Activation of CaM Kinases and Transcription Is Blocked by Vitamin D in MCF-7 Breast Cancer Cells

John¹,

Do²,

Amanda³

et al. 2017

JAMB

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Abstract. Calcium/calmodulin-dependent protein kinase (CaM Kinase) proteins are targets of hormones and growth factors and regulate cancer cell growth, apoptosis and migration. The hormone estrogen (E2) utilizes CaM Kinases to activate the Extracellular-signal regulated kinase (ERK) leading to MCF-7 breast cancer cell growth. The hormone Vitamin D (Vit D) may inhibit breast cancer cell growth however the cellular mechanisms of Vit D action remain to be elucidated. Within the present study we provide data that E2 stimulation of MCF-7 cells activates CaM Kinase Kinase (CaM KK), CaM KI, and ERK and the transcription factors Elk-1 and SRF. E2 treatment of MCF-7 cells potently stimulated Elk-1/SRF directed transcription of SRE-luciferase reporters. E2 activation of ERK, Elk-1, SRF and SRE-dependent luciferase activities were blocked by treating cells with the CaM KK inhibitor, STO-609, and the ERK inhibitor, U0126. Moreover, siRNAs directed against CaM KK and ERK blocked transcription factor phosphorylation and luciferase activity. Treatment of cells with Vit D, the hormone Epinephrine (Epi), or Forskolin, prevented E2 activation of CaM KK and ERK. Interestingly, Vit D promoted a PKA-dependent phosphorylation and inhibition of CaM KK as well as its association with 14-3-3. Epi and Vit D treatment of cells blocked the ability of E2 to active Elk-1 and SRE-luciferase activity. This data suggests an important role for CaM KK and ERK in regulating transcription downstream of E2 in MCF-7 cells. Our results also suggest that Vit D treatment of MCF-7 cells utilizes a unique PKA-dependent mechanism to block E2 activation of CaM KK, ERK and transcription.

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“…Third, there is direct binding between Akt and CaMKK based on coimmunoprecipitation assays. Fourth, calcium signaling has been shown to mediate Ca 2þ influx-induced Akt phosphorylation (22,23). Finally, a blockade of Akt activity has been shown to suppress castration-resistant growth in both mouse models and clinical settings (24)(25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Autocrine Activation of CHRM3 Promotes Prostate Cancer Growth and Castration Resistance via CaM/CaMKK–Mediated Phosphorylation of Akt

Wang

Yao

et al. 2015

Clinical Cancer Research

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Purpose: Although a previous study reported nerve endingderived acetylcholine promoted prostate cancer invasion and metastasis by regulating the microenvironment of cancer cells, the present study aims to determine whether there is autocrine cholinergic signaling in prostate epithelial cells that promotes prostate cancer growth and castration resistance.Experimental design: In this study, IHC was performed to detect protein expression in mouse prostate tissue sections and human prostate cancer tissue sections. Subcutaneously and orthotopically xenografted tumor models were established to evaluate the functions of autocrine cholinergic signaling in regulating prostate cancer growth and castration resistance. Western blotting analysis was performed to assess the autocrine cholinergic signaling-induced signaling pathway.Results: We found the expression of choline acetyltransferase (ChAT), the secretion of acetylcholine and the expression of CHRM3 in prostate epithelial cells, supporting the presence of autocrine cholinergic signaling in the prostate epithelium. In addition, we found that CHRM3 was upregulated in clinical prostate cancer tissues compared with adjacent noncancer tissues. Overexpression of CHRM3 or activation of CHRM3 by carbachol promoted cell proliferation, migration, and castration resistance. On the contrary, blockading CHRM3 by shRNA or treatment with darifenacin inhibited prostate cancer growth and castration resistance both in vitro and in vivo. Furthermore, we found that autocrine cholinergic signaling caused calmodulin/calmodulin-dependent protein kinase kinase (CaM/CaMKK)-mediated phosphorylation of Akt.Conclusions: These findings suggest that blockade of CHRM3 may represent a novel adjuvant therapy for castration-resistant prostate cancer.

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CaM kinase control of AKT and LNCaP cell survival

Cited by 20 publications

References 62 publications

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Estrogen Activation of CaM Kinases and Transcription Is Blocked by Vitamin D in MCF-7 Breast Cancer Cells

Autocrine Activation of CHRM3 Promotes Prostate Cancer Growth and Castration Resistance via CaM/CaMKK–Mediated Phosphorylation of Akt

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