Mitochondrial anchoring of PKCα by PICK1 confers resistance to etoposide-induced apoptosis

Wang, Wei Li; Yeh, Sheau Farn; Huang, Eagle Yi Kung; Lü, Yu; Wang, Chun Fa; Huang, Chi Ying F.; Lin, Wey Jinq

doi:10.1007/s10495-007-0098-0

Cited by 21 publications

(18 citation statements)

References 50 publications

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“…Several lines of evidence indicate that inhibition of PKCα is sufficient to induce apoptosis, suggesting that PKCα functions to suppress apoptosis in some cells (56,57). Overexpression of PKCα has been reported to promote the progression of breast cancer and reduce the expression of ER in MCF-7 cells (58).…”

Section: Discussionmentioning

confidence: 99%

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Xie

2012

Oncol Rep

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Abstract. This study was designed to investigate the role of protein kinase C (PKC) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in tamoxifen (TAM)-induced apoptosis and drug resistance in human breast cancer cells. Drug-sensitive, or estrogen receptor (ER)-positive human breast carcinoma cells (MCF-7) and the multi-drug-resistant variant (ER-negative) MCF-7/ADR cells were treated with doses of TAM for various periods of time. Cell viability and apoptosis were assessed using cell counting, DNA fragmentation and flow cytometric analysis. We found that TAM administration caused a significant increase in apoptosis of MCF-7 cells but not MCF-7/ADR cells. Western blot analysis revealed enhanced expression of PKCδ but decreased expression of PKCα in ER-positive MCF-7 cells; while ER-negative MCF-7/ADR cells had decreased levels of PKCδ and increased levels of PKCα. Interestingly, we observed that in MCF-7 cells, TAM stimulated apoptosis by promoting rapid activation of PKCδ, antagonizing downstream signaling of ERK phosphorylation; while in MCF-7/ADR cells, TAM upregulated PKCα, which promoted ERK phosphorylation. These results suggest that PKCδ enhances apoptosis in TAM-treated MCF-7 cells by antagonizing ERK phosphorylation; while the PKCα pathway plays an important role in TAM-induced drug resistance by activating ERK signaling in MCF-7/ADR cells. The combination of TAM with PKCα and ERK inhibitors could promote TAM-induced apoptosis in breast cancer cells. IntroductionBreast cancer is a common malignancy in females and the second cause of death from cancer in women today (1). Treatment for breast cancer includes surgery, chemotherapy, radiotherapy and endocrine therapy. Tamoxifen (TAM), an antagonist of the estrogen receptor (ER), is a selective ER modulator (SERM). TAM is a front-line endocrine therapeutic drug for ER-positive breast cancers. Results from TAM therapy showed a 40-50% reduction in the risk of cancer recurrence and cancer mortality (2). Recently, TAM has been demonstrated to be effective for some ER-negative breast cancers, as well as other types of cancers, including gliomas. These data suggest that TAM may also be implicated in ER-independent antitumor mechanisms (3,4). Of note, some advanced breast cancers that initially respond well to TAM eventually become refractory to treatment (5-9). Thus, the traditional mechanism of TAM action through the ER is challenged, and other noncanonical pathways need to be explored.Protein kinase C (PKC), a family of serine/threonine kinases, is involved in many important cellular functions, including cell proliferation, migration, differentiation, and apoptosis (10-12). Twelve PKC isoforms have been discovered in various cell types, including conventional PKCs (cPKCα, βI/βII and γ), novel PKCs (nPKCδ, ε, η), and atypical PKCs (aPKCζ) (13,14). The expression of PKCα, δ, ε, η, γ, μ, and ζ has been detected in MCF-7 cells (15,16); PKCα is a marker for anti-estrogen resistance and is involved in the growth of TAM-resistant human breast cancer cell...

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Section: Discussionmentioning

confidence: 99%

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Xie

2012

Oncol Rep

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“…PICK1 interaction with PKCα was shown to be involved in the mechanism of protection against etoposide-induced apoptosis, which was associated with the phosphorylation of Bcl-2. 153 …”

Section: Protein Kinase Cmentioning

confidence: 99%

Mitochondrial Protein Phosphorylation as a Regulatory Modality: Implications for Mitochondrial Dysfunction in Heart Failure

O’Rourke¹,

Eyk²,

Foster³

2011

Congestive Heart Failure

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Phosphorylation of mitochondrial proteins has been recognized for decades, and the regulation of pyruvate- and branched-chain α-ketoacid dehydrogenases by an atypical kinase/phosphatase cascade is well established. More recently, the development of new mass spectrometry-based technologies has led to the discovery of many novel phosphorylation sites on a variety of mitochondrial targets. The evidence suggests that the major classes of kinase and several phosphatases may be present at the mitochondrial outer membrane, intermembrane space, inner membrane, and matrix, but many questions remain to be answered as to the location, timing, and reversibility of these phosphorylation events and whether they are functionally relevant. The authors review phosphorylation as a mitochondrial regulatory strategy and highlight its possible role in the pathophysiology of cardiac hypertrophy and failure.

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“…Translocation of PKC isoforms, including PKC-␣, to mitochondria has been shown in several different cell types in response to a variety of different stimuli, including PMA, ischemia followed by reperfusion, heat shock, and toxicant exposure (10,41,42,43). PKC-␣ appears to be localized to the inner mitochondrial membrane and cristae and is specifically targeted and anchored to mitochondria by the protein interacting with C kinase (PICK1) (41,42). Mitochondrial localization of PKC-␣ is associated with its activation and resistance to drug-induced apoptosis in leukemia REH cells (35).…”

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confidence: 99%

Protein kinase C-α activation promotes recovery of mitochondrial function and cell survival following oxidant injury in renal cells

Nowak

Bakajsova

2012

American Journal of Physiology-Renal Physiology

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We demonstrated that nonselective PKC activation promotes mitochondrial function in renal proximal tubular cells (RPTC) following toxicant injury. However, the specific PKC isozyme mediating this effect is unknown. This study investigated the role of PKC-α in the recovery of mitochondrial functions in oxidant-injured RPTC. Wild-type PKC-α (wtPKC-α) and inactive PKC-α mutants were overexpressed in RPTC to selectively increase or block PKC-α activation. Oxidant (tert-butyl hydroperoxidel; TBHP) exposure activated PKC-α in RPTC but decreased PKC-α levels in mitochondria following treatment. Uncoupled and state 3 respirations and activities of complexes I and IV in TBHP-injured cells decreased to 55, 44, 49, and 65% of controls, respectively. F(0)F(1)-ATPase activity and ATP content in injured RPTC decreased to 59 and 60% of controls, respectively. Oxidant exposure increased reactive oxygen species (ROS) production by 210% and induced mitochondrial fragmentation and 52% RPTC lysis. Overexpressing wtPKC-α did not block TBHP-induced ROS production but improved respiration and complex I activity, restored complex IV and F(0)F(1)-ATPase activities, promoted recovery of ATP content, blocked mitochondrial fragmentation, and reduced RPTC lysis to 14%. In contrast, inhibiting PKC-α 1) induced mitochondrial hyperpolarization and fragmentation; 2) blocked increases in ROS production; 3) prevented recovery of respiratory complexes and F(0)F(1)-ATPase activities, respiration, and ATP content; and 4) exacerbated TBHP-induced RPTC lysis. We conclude that 1) activation of PKC-α prevents mitochondrial hyperpolarization and fragmentation, decreases cell death, and promotes recovery of mitochondrial respiration and ATP content following oxidant injury in RPTC; and 2) respiratory complexes I and IV and F(0)F(1)-ATPase are targets of active PKC-α.

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Mitochondrial anchoring of PKCα by PICK1 confers resistance to etoposide-induced apoptosis

Cited by 21 publications

References 50 publications

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Role of PKC-ERK signaling in tamoxifen-induced apoptosis and tamoxifen resistance in human breast cancer cells

Mitochondrial Protein Phosphorylation as a Regulatory Modality: Implications for Mitochondrial Dysfunction in Heart Failure

Protein kinase C-α activation promotes recovery of mitochondrial function and cell survival following oxidant injury in renal cells

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