Activation of Protein Kinase C by Phorbol 12-Myristate 13-Acetate suppresses the growth of lung cancer cells through KLF6 induction

Abstract

Phorbol 12-myristate 13-acetate (PMA) modulates cell proliferation and survival by activating several intracellular signaling pathways. Protein kinase C (PKC) plays a key role in PMA-induced growth arrest of non-small cell lung cancer (NSCLC) cells. Kruppel-like transcription factor 6 (KLF6), which is associated with negative control of cell proliferation, is downregulated in many cancers, including NSCLC. In this study, we found that KLF6 is downregulated in 17 lung cancer cell lines and in cells representing early stages of lung cancer development. Moreover, PMA induced cell growth arrest through KLF6 induction in H358 NSCLC cells. The increase in KLF6 by PMA was associated with upregulation of the cyclin-dependent kinase inhibitors (CDKIs) p21 WAF1/CIP1 and p27 KIP1 . In addition, inhibition of PKC or JNK activation decreased PMA-induced KLF6 induction and activation of PKC alone by Bryostatin-1 and Thymeleatoxin increased KLF6 levels. Moreover, siRNA-mediated knockdown of KLF6 reduced PMA-induced cell growth inhibition concomitantly with decreased expression of both p21 WAF1/CIP1 and p27 KIP1 , and in accordance, overexpression of KLF6 alone upregulated both CDKIs protein levels. Our results demonstrate the induction of the tumor suppressor KLF6 following PKC activation and its importance for PMA-mediated cancer cell growth arrest.

TPA-induced p21 expression augments G2/M arrest through a p53-independent mechanism in human breast cancer cells

“…TPA significantly increases cell proliferation in fibroblasts, epidermal cells, and several cancer cell lines, such as KG-1 human myeloblastic leukemia cells and ZR75-1 human breast cancer cells (22,23). However, TPA-induced activation of PKC suppresses the cell growth of non-small cell lung cancer cells and DanG pancreatic cancer cells (21,24). Although the role of TPA on the regulation of the cell cycle is controversial, we also found that TPA triggers the arrest of S to G2/M transition in MCF-7 and MDA-MB-231 breast cancer cells.…”

Biology of Krüppel‐like factor 6 transcriptional regulator in cell life and death

“…In this situation, KLF6 expression is induced and contributes to reduce cell proliferation rate, avoiding that it reach aberrant levels. In agreement, PMA-induced growth arrest of nonsmall cell lung cancer cells was mediated by induction of KLF6 expression following PKC activation (24). In addition, KLF6 mediates inhibition of cyclin D 1 /cyclin-dependent kinase 4 (cdk4) activity, resulting in growth inhibition (33).…”

“…Additionally, protein kinase C (PKC) has been associated with KLF6 increase following 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated growth arrest of nonsmall cell lung cancer cells. Moreover, activation of JNK and p38 pathways in lung cancer cells is downstream effectors for KLF6 protein rise on PKC induction (24). Moreover, regulation of KLF6 transcriptional activity and halflife through direct acetylation (25) and proteasome-mediated degradation (25,26), respectively, have been reported.…”

Mechanism of interferon-gamma production by monocytes stimulated with myeloperoxidase and neutrophil extracellular traps

“…However, PMA itself induces cytokine production by monocytes. Nuclear factor kappa-B (NF-kB) [21,22] and protein kinase C [23] have long been considered to mediate a prototypical proinflammatory signaling pathway, and PMA is a specific activator of both protein kinase C and NF-κB [24][25][26]. PMA induces the phosphorylation of extracellular signal-regulated kinase (ERK), which is dependent on the protein kinase C alpha pathway [27,28].…”