Variable expression of protein kinase Cε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis

Gillespie, Susan; Zhang, Xu Dong; Hersey, Peter

doi:10.1158/1535-7163.mct-04-0332

Cited by 40 publications

(44 citation statements)

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“…2,10,[15][16][17][18] Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinases, is emerging as a critical regulator of cellular responses to TRAIL. 12,14,[18][19][20][21][22][23][24] The PKC family consists of 11 isoforms that are classified as conventional (a, b1, b2 and g), novel (d, e, Z and y) or atypical (z and i/l). 25 PKCs are involved in the regulation of cell proliferation, differentiation as well as cell death.…”

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“…23,29,30 Activation of PKC was shown to protect against TRAILinduced apoptosis in several cell lines, including cervical cancer, multiple myeloma, glioma and breast cancer. 19,20,22,23 There are conflicting reports as to the mechanisms by which PKC exerts its protective effect. In cervical cancer HeLa cells, PKC activation hindered apical events in the TRAIL receptor-mediated pathway by interfering with FADD recruitment to the DISC.…”

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“…12,14 In melanoma and breast cancer MCF-7 cells, PKC acted upstream of mitochondria but downstream of caspase-8 and Bid. 19,22 In the latter study, the effect of phorbol myristic acetate (PMA) was examined but the contribution of a specific PKC isoform was not tested. The mechanism of TRAIL resistance may vary depending on the PKC isozyme.…”

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confidence: 99%

“…The mechanism of TRAIL resistance may vary depending on the PKC isozyme. 14,18,19,24,31 PKCe has been implicated in inhibiting TRAIL-induced apoptosis in glioma and melanoma cells. 18,19,23 Increased levels and activity of PKCe were associated with TRAIL resistance, 19 and overexpression of PKCe inhibited TRAILinduced apoptosis in these cells.…”

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“…14,18,19,24,31 PKCe has been implicated in inhibiting TRAIL-induced apoptosis in glioma and melanoma cells. 18,19,23 Increased levels and activity of PKCe were associated with TRAIL resistance, 19 and overexpression of PKCe inhibited TRAILinduced apoptosis in these cells. 18,23 It has been reported that cellular susceptibility to TRAIL cannot be explained by the status of TRAIL receptor expression but does correlate with PKCe level.…”

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Downregulation of Bid is associated with PKCɛ-mediated TRAIL resistance

2006

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent as it selectively kills tumor cells but spares normal cells. Resistance to TRAIL by tumor cells limits its therapeutic use. We have previously shown that protein kinase C-e (PKCe) acts as an antiapoptotic protein in MCF-7 breast cancer cells. In the present study, we have investigated the mechanism(s) by which PKCe contributes to TRAIL resistance. Overexpression of PKCe inhibited caspase-8 and -9 activation, release of mitochondrial cytochrome c and cell death induced by TRAIL, but did not interfere with the recruitment of caspase-8 to the death-inducing signaling complex. Knockdown/inhibition of PKCe resulted in enhanced sensitivity to TRAIL. The level of Bcl-2 was increased and Bid was decreased by PKCe at both the protein and mRNA level but PKCe had no effect on Bax. Knockdown of Bcl-2 by siRNA reversed TRAIL resistance in PKCe-overexpressing cells, whereas depletion of Bid contributed to TRAIL resistance in MCF-7 cells. A decrease in Bid content was also associated with inhibition of TRAIL-induced caspase-8 activation. Furthermore, PKCe depletion or overexpression of DN-PKCe was associated with a decrease in Bcl-2 protein level. Thus, our results suggest that PKCe acts upstream of mitochondria and mediates TRAIL resistance via both Bcl-2 and Bid in MCF-7 cells.

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Downregulation of Bid is associated with PKCɛ-mediated TRAIL resistance

2006

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Overcoming Resistance to Apoptosis in Cancer Therapy

Hersey

Zhang

Mhaidat

2008

Advances in Experimental Medicine and Biology

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Protein Kinase C and Apoptosis

Reyland

Apoptosis, Cell Signaling, and Human Diseases

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The protein kinase C (PKC) family consists of ten structurally related serine/threonine protein kinases. PKC isoforms are critical regulators of cell proliferation and survival and their expression or activity is altered in some human diseases, particularly cancer. The development and utilization of PKC isoform specific tools, including dominant inhibitory kinases, mouse models in which specific PKC isoforms have been disrupted, and PKC isoform specific antisense/siRNA, has allowed studies to define isoform-specific functions of PKC in the apoptotic pathway. From these approaches a pattern is emerging in which the conventional isoforms, particularly PKC and PKC , and the atypical PKCs, PKC / and PKC , appear to be anti-apoptotic/pro-survival. The novel isoform, PKC , is primarily pro-apoptotic, whereas PKC in most studies appears to suppress apoptosis. The identification of both pro-and anti-apoptotic isoforms suggests that PKC isoforms may function as molecular sensors, promoting cell survival under favorable conditions, and executing the death of abnormal or damaged cells when needed.This chapter discusses what is currently known about the contribution of specific isoforms to apoptosis, and how signal transduction by PKC integrates with other molecular regulators to promote or inhibit apoptosis.

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Variable expression of protein kinase Cε in human melanoma cells regulates sensitivity to TRAIL-induced apoptosis

Abstract: Protein kinase C (PKC) activation is believed to protect against apoptosis induced by death receptors. We have found however that the effect of activation of PKC on tumor necrosis factor -related apoptosis-inducing ligand (TRAIL)

Cited by 40 publications

References 33 publications

Downregulation of Bid is associated with PKCɛ-mediated TRAIL resistance

Downregulation of Bid is associated with PKCɛ-mediated TRAIL resistance

Overcoming Resistance to Apoptosis in Cancer Therapy

Protein Kinase C and Apoptosis

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