Regulation of TRAIL-mediated apoptosis by PKCK2 in cancer cell lines

Abstract

[한글]

[영문]

Protein kinase casein kinase 2 (PKCK2) is a serine/threonine kinase that has been known to play important roles in cell cycle control, cellular differentiation, and proliferation. Recently, it was reported that intracellular high PKCK2 activity prevents cancer cells from undergoing apoptosis through phosphorylating procaspase-2. When PKCK2 activity is down-regulated by specific inhibitor, procaspase-2 is activated, procaspase-8 is processed by active caspase-2, and then, TRAIL-resistant cancer cells become primed for TRAIL-mediated apoptosis. To examine whether PKCK2-dependent mechanism for TRAIL resistance of cancer cells could be generalized, endogenous PKCK2 activity and TRAIL sensitivity were correlated using 17 human cancer cell lines originated from stomach and liver. Among the 17 cancer cell lines, 11 cell lines (64.7%) corresponded with the mechanism while 6 cell lines (35.3%) did not: 5 cell lines (MKN-45, MKN-74, SNU484, SNU719, SNU886) showed ‘low PKCK2 activity - high TRAIL sensitivity’, 6 cell lines (AGS, MKN-1, MKN-28, Hep3B, SK-HEP-1, SNU739) showed ‘high PKCK2 activity - low TRAIL sensitivity’, 4 cell lines (NCI-N87, HepG2, SNU761, SNU878) showed ‘low PKCK2 activity - low TRAIL sensitivity’ and 2 cell lines (SNU638, SNU668) showed ‘high PKCK2 activity ? high TRAIL sensitivity’. 6 cell lines (AGS, MKN-1, MKN-28, Hep3B, SK-HEP-1, SNU739) that showed ‘high PKCK2 activity - low TRAIL sensitivity’ were sensitized to TRAIL by inhibiting PKCK2 activity. The expression profiles of pro- or anti-apoptotic molecules of cancer cell lines were examined to get insights why PKCK2 activity and TRAIL sensitivity did not correlated in some cancer cell lines. Some cancer cells expressed pro- or anti-apoptotic molecules at too low or too high level to induce apoptosis. Among the molecules, procaspase-8 was focused especially. PKCK2 phosphorylated procaspase-8 at threonine-373, and the phosphorylation inhibited processing of procaspase-8 by active caspase-2. Taken together, intracellular PKCK2 activity determines TRAIL sensitivity in several cancer cell lines and PKCK2 regulates TRAIL sensitivity of cancer cells by phosphorylating procaspase-8.