High Expression of Atypical Protein Kinase C λ/ι in Gastric Cancer as a Prognostic Factor for Recurrence

Takagawa, Ryo; Akimoto, Kazunori; Ichikawa, Yasushi; Akiyama, Hirotoshi; Kojima, Yasuyuki; Ishiguro, Hitoshi; Inayama, Yoshiaki; Aoki, Ichiro; Kunisaki, Chikara; Endo, Itaru; Nagashima, Yoji; Ohno, Shigeo

doi:10.1245/s10434-009-0708-x

Cited by 51 publications

(60 citation statements)

References 41 publications

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“…We propose that the tumor suppressor function of PAR3 stems, at least in part, from its role in restricting the activity of aPKC. This model is consistent with the reported oncogenic activity of aPKC (8,46,47).…”

Section: Discussionsupporting

confidence: 92%

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

Guyer

Macara

2015

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 92%

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

Guyer

Macara

2015

Journal of Biological Chemistry

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“…10,11 Importantly, the PKCl/i gene is located at the 3q26.2 genomic region, which is most frequently amplified in human cancer 16,17 , and overexpression of PKCl/i has been implicated in cancer development in multiple tissues including the lung, 18,19 pancreas, 20 stomach, 21 colon, 22 esophagus, 23 liver, 24 bile duct, 25 ovary, 17 prostate 26 and brain. 27 Recently, few studies have been reported higher expression of PKCl/i in ER/PRand HER-positive breast cancer and also in lymph node metastases.…”

mentioning

confidence: 99%

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

et al. 2014

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Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCk/i, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCk/i signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCk/i signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCk/i expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCk/i significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCk/i-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFb and IL1b could activate PKCk/i signaling in TNBC cells and depletion of PKCk/i impairs NF-jB p65 (RelA) nuclear localization. We observed that cytokine-PKCk/i-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCk/i promote TNBC growth, invasion and metastasis. Thus, targeting PKCk/i signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

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“…Note PKCι overexpression has been observed in numerous human cancers including cancers of the lung (Regala et al, 2005b), pancreas (Scotti et al, 2010), stomach (Takagawa et al, 2010), colon (Murray et al, 2004), esophagus (Yang et al, 2008), liver (Du et al, 2009), bile duct (Li et al, 2008), breast (Kojima et al, 2008), ovary (Weichert et al, 2003;Eder et al, 2005;Zhang et al, 2006), prostate (Ishiguro et al, 2009), and brain (Patel et al, 2008). PKCι is itself an oncogene, which appears to be activated through tumor-specific overexpression.…”

Section: Various Cancersmentioning

confidence: 99%

PRKCI (protein kinase C, iota)

Justilien¹,

Fields²

2012

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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High Expression of Atypical Protein Kinase C λ/ι in Gastric Cancer as a Prognostic Factor for Recurrence

Abstract: Our results suggested that aPKClambda/iota overexpression was a strong prognostic factor for gastric adenocarcinoma recurrence. As well as being a new prognostic indicator, aPKClambda/iota is also likely to be a novel therapeutic target for gastric cancer.

Cited by 51 publications

References 41 publications

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

Loss of the Polarity Protein PAR3 Activates STAT3 Signaling via an Atypical Protein Kinase C (aPKC)/NF-κB/Interleukin-6 (IL-6) Axis in Mouse Mammary Cells

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

PRKCI (protein kinase C, iota)

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