Activation of conventional PKC isoforms increases expression of the pro-apoptotic protein Bad and TRAIL receptors

Int J Gastrointest Cancer. 2002;32(2-3):63-72. doi: 10.1385/IJGC:32:2-3:63.


Background: Pancreatic cancer is a leading cause of cancer death worldwide; current treatment options have been ineffective in prolonging survival. Agents that target specific signaling pathways (e.g., protein kinase C [PKC]) may regulate apoptotic gene expression rendering resistant cancers sensitive to the effects of other chemotherapeutic drugs. The purpose of our study was to assess the effect of PKC stimulation on apoptotic gene expression in pancreatic cancer cells.

Methods: The human pancreatic cancer cell line, PANC-1, was treated with PKC-stimulating agents, phorbol 12-myristate 13-acetate (PMA) or bryostatin-1, and analyzed for expression of apoptosis-related genes.

Results: Both PMA and bryostatin-1 induced expression of the pro-apoptotic gene Bad in a dose dependent fashion. The expression of Bad was blocked by the PKC inhibitors GF109203x, Gö6983, and Ro-31-8220, suggesting a role for the conventional isoforms of PKC. In addition, treatment with the MEK inhibitors PD98059 or UO126 reduced PMA-mediated induction of Bad gene expression. PMA also increased the expression of TRAIL receptors DR4 and DR5; this expression was inhibited by the PKC inhibitors GF109203x, Gö6983, and Ro-31-8220 and the MEK inhibitor UO126, suggesting a role for conventional PKC isoforms and MEK in the regulation of TRAIL receptor expression.

Conclusions: PKC stimulation in PANC-1 cells increases expression of the pro-apoptotic gene Bad and the TRAIL receptors, DR4 and DR5, through both conventional PKC- and MEK-dependent pathways. Agents that stimulate PKC may sensitize pancreatic cancer cells to apoptosis and provide a potential adjuvant therapy for the treatment of chemoresistant pancreatic cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Carrier Proteins / biosynthesis*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Isoenzymes
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / physiopathology*
  • Protein Kinase C / chemistry
  • Protein Kinase C / pharmacology*
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Tumor Necrosis Factor / biosynthesis*
  • Tumor Cells, Cultured
  • bcl-Associated Death Protein


  • BAD protein, human
  • Carrier Proteins
  • Isoenzymes
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Tumor Necrosis Factor
  • bcl-Associated Death Protein
  • Protein Kinase C