Protein kinase C alpha‐dependent signaling mediates endometrial cancer cell growth and tumorigenesis

Abstract

Endometrial cancer is the most common invasive gynecologic malignancy, yet molecular mechanisms and signaling pathways underlying its etiology and pathophysiology remain poorly characterized. We sought to define a functional role for the protein kinase C (PKC) isoform, PKCa, in an established cell model of endometrial adenocarcinoma. Ishikawa cells depleted of PKCa protein grew slower, formed fewer colonies in anchorage-independent growth assays and exhibited impaired xenograft tumor formation in nude mice. Consistent with impaired growth, PKCa knockdown increased levels of the cyclin-dependent kinase (CDK) inhibitors p21 Cip1/WAF1 (p21) and p27 Kip1 (p27). Despite the absence of functional phosphatase and tensin homolog (PTEN) protein in Ishikawa cells, PKCa knockdown reduced Akt phosphorylation at serine 473 and concomitantly inhibited phosphorylation of the Akt target, glycogen synthase kinase-3b (GSK-3b). PKCa knockdown also resulted in decreased basal ERK phosphorylation and attenuated ERK activation following EGF stimulation. p21 and p27 expression was not increased by treatment of Ishikawa cells with ERK and Akt inhibitors, suggesting that PKCa regulates CDK expression independently of Akt and ERK. Immunohistochemical analysis of Grade 1 endometrioid adenocarcinoma revealed aberrant PKCa expression, with foci of elevated PKCa staining, not observed in normal endometrium. These studies demonstrate a critical role for PKCa signaling in endometrial tumorigenesis by regulating expression of CDK inhibitors p21 and p27 and activation of Akt and ERK-dependent proliferative pathways. Thus, targeting PKCa may provide novel therapeutic options in endometrial tumors. ' 2009 UICC

K562 cell proliferation is modulated by PLCβ1 through a PKCα-mediated pathway

“…[19][20][21] Several evidences indicate PKCs as key regulators of critical cell cycle phases, including G 0 -G 1 /S transition and G 2 /M progression. [16][17][18]22 Among them, PKCα, already reported to be part of PLCβ1 signaling, 11,13,23 is known for its involvement in G 1 /S transition. 24 It has been demonstrated that, in intestinal epithelial cells, an anti-proliferative regulation of Cyclin D1 was modulated by PKCα signaling.…”

“…28,29 In detail, cyclin inhibitors such as p21/Cip1 and p27/Kip1, known to be necessary for cell cycle progression, [30][31][32] are often targeted by PKCs. 22,28,29,33 Here, we aimed to investigate the proliferation of Figure 1. overexpression of both pLCβ1 isoforms specifically modulates cyclin D3 protein levels in proliferating K562 cells.…”

“…As reported in the literature, PKCs are often involved in cell proliferation targeting key proteins of cell cycle regulation, such as cyclins, cyclin-dependent kinases and cyclin inhibitors like p21/Cip1 and p27/Kip1. 16,22,[30][31][32]40,41 The most expressed PKC isoforms in K562 cells are the conventional PKCα and PKCβII and the atypical PKCζ. 42 For this reason, we screened their levels in cells overexpressing PLCβ1 to evaluate if these PKC isoforms could be affected.…”

Early Endosomal Antigen 1 (EEA1) Is an Obligate Scaffold for Angiotensin II-induced, PKC-α-dependent Akt Activation in Endosomes

“…Next, we examined the effects of EEA1 silencing upon the following: activation of PDK1, a well established kinase for Akt Thr-308 phosphorylation (48 -50); p38 MAPK, which was reported as a kinase upstream of Akt Ser-473 (51); and PKC-␣, which was recently established as an Akt regulator (24,52). We first examined whether these kinases are recruited to EEA1 endosomes in response to Ang II.…”

Osteoporosis as a Novel Marker of Uterine Cancer Risk Factor

“…It is the third most common cancer in females after breast and ovarian cancer and carry a high death rate (Yang et al, 2011). Although a large number of women affected, the pathophysiological mechanisms is still largely unknown (Haughian et al, 2009).…”