Anti-proliferative effects of novel T-type calcium channel blocker KCP10043F in human pancreatic cancer cells through Ca2+/CaMKII pathway via ER stress induction

초록

Pancreatic cancer is among the most lethal cancer types with a 5-year survival rate of approximately 5 %. Although a T-type calcium channel blocker, 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3(N,N-dimethylureido)-N '-methylpropylamino]-3,4-dihydroquinazoline (KCP10043F, OZ-001), previously exhibited the anti-tumor effects in lung cancer, its anti-proliferative effects and the specific molecular mechanisms in pancreatic cancer remain unclear. This study was conducted to evaluate the anti-proliferative effects of KCP10043F on human pancreatic cancer cell lines, PANC-1 and MIA PaCa-2. 1) KCP10043F suppressed cell growth and colony formation, and promoted the G1 phase cell retention by downregulating G1 phase-related proteins; 2) KCP10043F triggered apoptotic cell death via the intrinsic pathway by upregulating BH3-only Bcl-2 family proteins; 3) At the molecular level, KCP10043F inhibited the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (p70S6K) pathway and activated the c-Jun Nterminal kinase (JNK)/c-Jun pathway; 4) KCP10043F mediated the Ca2+/Calcium-calmodulin-dependent kinase II (CaMKII) pathway by inducing endoplasmic reticulum (ER) stress; 5) alpha-Tocopherol controlled KCP10043Finduced cell cycle arrest and apoptosis by attenuating ER stress. These results demonstrate the potential of KCP10043F as a therapeutic candidate for human pancreatic cancer.

키워드