Enhancement of anchorage-independent growth of human pancreatic carcinoma MIA PaCa-2 cells by signaling from protein kinase C to mitogen-activated protein kinase
✍ Scribed by Keiko Ishino; Hidesuke Fukazawa; Mayumi Shikano; Motoi Ohba; Toshio Kuroki; Yoshimasa Uehara
- Publisher
- John Wiley and Sons
- Year
- 2002
- Tongue
- English
- Weight
- 222 KB
- Volume
- 34
- Category
- Article
- ISSN
- 0899-1987
- DOI
- 10.1002/mc.10063
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✦ Synopsis
Abstract
We found that 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) promoted anchorage‐independent growth but did not affect anchorage‐dependent growth of MIA PaCa‐2 human pancreatic carcinoma cells. TPA markedly activated mitogen‐activated protein kinase (MAPK)/extracellular signal–regulated kinase in an anchorage‐independent manner. Two protein kinase C (PKC) isoforms, conventional PKC (cPKC) and novel PKC (nPKC), but not apical PKC, translocated from the cytosolic to the particulate fraction upon TPA treatment. To identify the PKC isoforms involved in the regulation of anchorage‐independent growth, four PKC isoforms (α, δ, ε, and ζ) were forced to be expressed in MIA PaCa‐2 cells with an adenovirus vector. Overexpression of nPKCδ or nPKCε activated MAPK and promoted anchorage‐independent growth. Overexpression of cPKCα alone did not influence anchorage‐independent growth but lowered the concentration of TPA that was required to enhance such growth. Expression of constitutively active MAPK kinase‐1 (MEK1) also promoted anchorage‐independent growth. Furthermore, PKC inhibitors or an MEK inhibitor completely suppressed both TPA‐induced activation of MAPK and promotion of anchorage‐independent growth, but a cPKC‐selective inhibitor partially suppressed TPA‐induced promotion of the growth. Based on these results, we suggest that MAPK activation, mediated by certain isoforms of PKC, plays a part in oncogenic growth of MIA PaCa‐2 cells. In summary, our data indicated that specific inhibitors of the cPKC and nPKC signaling pathway might be selective anti‐oncogenic growth agents for some types of human pancreatic cancer. © 2002 Wiley‐Liss, Inc.