Tetrandrine inhibits deregulated cell cycle in pancreatic cancer cells: Differential regulation of p21Cip1/Waf1, p27Kip1 and cyclin D1

Karnika Singh; Qin Dong; Prakash S TimiriShanmugam; Sweaty Koul; Hari K Koul

doi:10.1016/j.canlet.2018.03.042

Tetrandrine inhibits deregulated cell cycle in pancreatic cancer cells: Differential regulation of p21^Cip1/Waf1, p27^Kip1 and cyclin D1

Cancer Lett. 2018 Jul 1:425:164-173. doi: 10.1016/j.canlet.2018.03.042. Epub 2018 Mar 30.

Authors

Karnika Singh¹, Qin Dong², Prakash S TimiriShanmugam², Sweaty Koul³, Hari K Koul⁴

Affiliations

¹ Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA; Feist Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
² Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
³ Department of Urology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA; Feist Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA, 71130, USA.
⁴ Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130, USA; Overton Brooks Veterans Administrative Medical Center, 510 E Stoner Ave, Shreveport, LA, 71101, USA; Feist Weiller Cancer Center, 1501 Kings Highway, Shreveport, LA, 71130, USA. Electronic address: hkoul@lsuhsc.edu.

PMID: 29605511
DOI: 10.1016/j.canlet.2018.03.042

Abstract

Current therapies in Pancreatic Cancer (PaCa) are ineffective due to deregulated cell cycle driven by landscape mutations. In this study, we show for the first time that tetrandrine (TET) inhibits proliferation of the PaCa cells and inhibits PaCa tumor growth. TET inhibits cell cycle transition at G1/S boundary. TET increased levels of p21^Cip1/Waf1 and p27^Kip1, had no effect on the levels of CDK4/6 proteins and decreased the levels of cyclin D1 and pRb proteins. TET resulted in changes in mRNA levels of cyclin D1 and p21^Cip1/Waf1 but had no effect on the mRNA of p27^Kip1. We show, for the first time in any system, that TET treatment downregulated Skp2, E3 ligase specific for degradation of p27^Kip1 during the cell cycle. Taken together our results show, that TET indirectly impairs the activities of CDK4/6 to halt deregulated cell cycle and inhibit PaCa tumor growth. These results suggest that TET may serve as a novel agent for treatment of PaCa, for which there is no effective cure to date.

Keywords: Cell cycle inhibition; Pancreatic cancer; Skp2; Tetrandrine; p21(Cip1/Waf1); p27(Kip1).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / administration & dosage*
Antineoplastic Agents, Phytogenic / pharmacology
Benzylisoquinolines / administration & dosage*
Benzylisoquinolines / pharmacology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cyclin D1 / genetics*
Cyclin D1 / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / genetics*
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / genetics*
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Gene Expression Regulation, Neoplastic / drug effects
Humans
Mice
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Promoter Regions, Genetic
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Phytogenic
Benzylisoquinolines
CCND1 protein, human
CDKN1A protein, human
CDKN1B protein, human
Cyclin-Dependent Kinase Inhibitor p21
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p27
tetrandrine