Abstract
We have previously shown that parotid C5 salivary acinar cells undergo apoptosis in response to etoposide treatment as indicated by alterations in cell morphology, caspase-3 activation, DNA fragmentation, sustained activation of c-Jun N-terminal kinase, and inactivation of extracellular regulated kinases 1 and 2. Here we report that apoptosis results in the caspase-dependent cleavage of protein kinase C-delta (PKCdelta) to a 40-kDa fragment, the appearance of which correlates with a 9-fold increase in PKCdelta activity. To understand the function of activated PKCdelta in apoptosis, we have used the PKCdelta-specific inhibitor, rottlerin. Pretreatment of parotid C5 cells with rottlerin prior to the addition of etoposide blocks the appearance of the apoptotic morphology, the sustained activation of c-Jun N-terminal kinase, and inactivation of extracellular regulated kinases 1 and 2. Inhibition of PKCdelta also partially inhibits caspase-3 activation and DNA fragmentation. Immunoblot analysis shows that the PKCdelta cleavage product does not accumulate in parotid C5 cells treated with rottlerin and etoposide together, suggesting that the catalytic activity of PKCdelta may be required for cleavage. PKCalpha and PKCbeta1 activities also increase during etoposide-induced apoptosis. Inhibition of these two isoforms with Gö6976 slightly suppresses the apoptotic morphology, caspase-3 activation, and DNA fragmentation, but has no effect on the sustained activation of c-Jun N-terminal kinase or inactivation of extracellular regulated kinase 1 and 2. These data demonstrate that activation of PKCdelta is an integral and essential part of the apoptotic program in parotid C5 cells and that specific activated isoforms of PKC may have distinct functions in cell death.
Highlights
Apoptosis is important for the destruction of tumor cells and cells damaged by viral infection, drugs, chemical radiation, and aging [1,2,3,4]
Changes in the Expression of Specific protein kinase C (PKC) Isoforms Occur during Etoposide-induced Apoptosis—Apoptosis occurs in a series of well defined steps that involve specific biochemical changes to the cell
In this report we show that PKC␦ is activated in a caspase-dependent manner in parotid salivary acinar cells induced to undergo apoptosis by chemotherapeutic drugs
Summary
Apoptosis is important for the destruction of tumor cells and cells damaged by viral infection, drugs, chemical radiation, and aging [1,2,3,4]. The critical genes in the apoptotic process have been defined genetically in Caenorhabditis elegans and biochemically in other species [9] These include the Bcl-2 family of proteins, a family of related regulatory proteins, which either promote or suppress apoptosis [10], and the caspases, cysteine proteases that are responsible for initiation and execution of the apoptotic signal [11]. The atypical PKC isoforms, PKC and PKC, have likewise been shown to protect against apoptosis in many cell types [33,34,35]. In support of a pro-apoptotic role for PKC, activation of PKC with phorbol 12-myristate 13-acetate, or overexpression of PKC␣, can induce apoptosis in prostatic carcinoma cells [36, 37]. Protein Kinase C-␦ Is Essential for Salivary Cell Apoptosis cells in response to agents that induce apoptosis [44]
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