Phorbol ester-induced apoptosis of C4-2 cells requires both a unique and a redundant protein kinase C signaling pathway

Lihong Yin, Nabila Bennani-Baiti, C. Thomas Powell

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Phorbol 12-myristate 13-acetate (PMA) potently induces apoptosis of LNCaP human prostate cancer cells. Here, we show that C4-2 cells, androgen- hypersensitive derivatives of LNCaP cells, also are sensitive to PMA-induced apoptosis. Previous reports have implicated activation of protein kinase C (PKC) isozymes α and δ in PMA-induced LNCaP apoptosis using overexpression, pharmacological inhibitors, and dominant-negative constructs, but have left unresolved if other isozymes are involved, if there are separate requirements for individual PKC isozymes, or if there is redundancy. We have resolved these questions in C4-2 cells using stable expression of short hairpin RNAs to knock down expression of specific PKC isozymes individually and in pairs. Partial knockdown of PKCδ inhibited PMA-induced C4-2 cell death almost completely, whereas near-complete knockdown of PKCα had no effect. Knockdown of PKCε alone had no effect, but simultaneous knockdown of both PKCα and PKCε in C4-2 cells that continued to express normal levels of PKCδ inhibited PMA-induced apoptosis. Thus, our data indicate that there is an absolute requirement for PKCδ in PMA-induced C4-2 apoptosis but that the functions of PKCα and PKCε in apoptosis induction are redundant, such that either one (but not both) is required. Investigation of PMA-induced events required for LNCaP and C4-2 apoptosis revealed that p38 activation is dependent on PKCδ, whereas induction of retinoblastoma protein hypophosphorylation requires both PKC signaling pathways and is downstream of p38 activation in the PKCδ pathway.

Original languageEnglish (US)
Pages (from-to)5533-5541
Number of pages9
JournalJournal of Biological Chemistry
Issue number7
StatePublished - Feb 18 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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