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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 5  |  Page : 74-79

Protein kinase Cs in lung cancer: A promising target for therapies


1 People’s Military Medical Press, Beijing, 100036, China
2 Sbarro Institute for Cancer Research and Molecular Medicine and Center of Biotechnology, College of Science and Technology Temple University, BioLife Science Bldg. Suite 431, 1900 N 12th Street, Philadelphia, PA 19122, USA

Date of Web Publication30-Sep-2013

Correspondence Address:
Yong Li
People’s Military Medical Press, Beijing, 100036
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.119102

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 > Abstract 

Lung cancer has been identified as one of the most deadly oncologies. The most influential causes for disease progression include smoking, genetic mutation and inflammatory lung diseases. Conventional therapies for lung cancer including chemo and radio-treatments often cause serious adverse effects. The advent of novel therapeutics that specifically target signalling pathways activated by genetic alterations has revolutionized the way patients with lung cancer are treated. These are comprised of various molecular targets on its carcinogen signalling pathways, among which the protein kinase C (PKC) family is a promising target. The 12 isotypes in the family demonstrate complex interactions. This inter-linked signalling loop has added complexity of developing effective therapies. An improved understanding of different molecules involved in these signalling pathways will provide several profound implications, ranging from preclinical work on the mechanisms to trial design. Therapies developed targeting individual/multiple PKCs combined with conventional strategies offer promising future combating cancer.

Keywords: Combined anti-cancer therapies, lung cancer, protein kinase Cs


How to cite this article:
Fan C, Li Y, Jia J. Protein kinase Cs in lung cancer: A promising target for therapies. J Can Res Ther 2013;9, Suppl S1:74-9

How to cite this URL:
Fan C, Li Y, Jia J. Protein kinase Cs in lung cancer: A promising target for therapies. J Can Res Ther [serial online] 2013 [cited 2019 Aug 24];9:74-9. Available from: http://www.cancerjournal.net/text.asp?2013/9/5/74/119102


 > Introduction Top


Lung carcinoma is the leading cause of cancer-related death world-wide. It is a disease characterized by uncontrolled cell growth in tissues of the lung. The primary lung cancers are carcinomas that derive from epithelial cells. The main types of lung cancer are small-cell lung carcinoma (SCLC), and non-small-cell lung carcinoma (NSCLC). Approximately, 20% of lung cancer cases are SCLC by histology, with the other 80%, which includes adenocarcinoma, squamous cell carcinoma, large-cell carcinoma and bronchoalveolar cell carcinoma, being lumped together as NSCLC. [1] Although the primary lung cancer commonly metastasizes to the brain, bones, liver and adrenal glands, secondary cancers are happening with high incidence and can be derived from various sites. [2] The pathology of lung cancer has not been fully understood, yet, about 85% of cases are related to cigarette smoking, the rest of pathological initiatives include genetic mutations, environmental stimulus as well as other lung diseases such as chronic obstructive pulmonary disease (COPD).

Among its carcinogen signaling pathways, the protein kinase C (PKC) family plays an important role. [3] PKCs is a kinase family composed of 12 identified isoforms so far. PKCs have various functions and are widely expressed in vivo. PKC are activated through various signaling pathways and is abundant in cells. They regulate a diverse range of disease progression. The increased activation of PKC isozymes has been observed in cancer, diabetes, ischemic heart disease, heart failure, lung and kidney diseases, various dermatological diseases (including psoriasis) as well as autoimmune diseases; increased PKC activation has also been implicated in psychiatric diseases, including bipolar disorder, and in several neurological indications such as stroke, Parkinson's disease, dementia, Alzheimer's disease and pain [Table 1]. [4] The regulation role of PKCs in cancers is becoming increasingly clear. [5] In this review, we will discuss the pathological progression of lung cancer as well as PKCs family as an effective target for lung cancer therapies.
Table 1: The function of protein kinase C isoforms in the disease

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 > The Primary Pathological Causes of Lung Cancer Top


The tumor-promoting activities of tobacco smoke and its condensate have been clearly demonstrated through administration both by inhalation and by application to mouse skin. [6] Tumor promoters are not carcinogenic themselves, but they enhance the activity of carcinogens when given subsequently. Several pro-inflammatory changes have been observed in smokers' lungs and inflammation is closely associated with tumor promotion and activation of factors such as nuclear factor-κB. [7],[8],[9] Inflammation has a role in smoking-associated COPD, [10] and COPD (especially emphysema) is, in turn, an independent risk factor for lung cancer. [11]

COPD is comprised of two major components - the obstruction of the breathing tubes (airways disease) and the obliteration of the tiny air sacs in the peripheral regions of the lung (emphysema). [12] Lung cancer is considerably less common than COPD, yet, COPD seems to be linked to all the subtypes of lung cancer. [13],[14] However, there are still several unanswered questions regarding the links between COPD and lung cancer. Furthermore, PKCs, play an important role in COPD progression. [15] The common morphological changes: Hypersecretion of mucous results from hypertrophy of submucosal mucous glands and increased numbers of goblet cells in bronchiolar epithelium were attenuated with the pan PKC inhibitor, calphostin. [16] The evidence suggested PKC inhibitor as important interventions for the progression of COPD and thus lung cancer.

In lung cancer, the essential genetic mutations leading to cell proliferation or evasion from apoptosis is in the epidermal growth factor receptor (EGFR). [17],[18],[19],[20] Spontaneous EGFR mutations often are oncogenic; that is, they activate the EGFR-signaling pathway in the absence of ligand and promote cell proliferation, survival and anti-apoptotic signals. Inhibition of EGFR leads to up-regulation of pro-apoptotic molecules and finally results in cell death through the activation of the intrinsic mitochondrial apoptotic pathway. [21],[22] Somatic mutations in the EGFR gene result in a state of constitutive activation of the receptor, signaling to the cell to proliferate and to resist apoptosis. Recently, Dittmann, et al.[23] described the role of PKCε in phosphorylation of EGFR, which is a key step in translocation of EGFR to the nucleus, where it induces the transcription of genes essential for cell survival after stress exposure. It indicates that PKCs might be an important regulator in lung cancer.


 > Pkc: A Key Modulator in Lung Cancer Progression Top


PKC was originally identified as a phospholipid-and calcium-dependent protein kinase (PK). [24] There are three subfamilies of PKCs: Conventional or classic PKCs, non-classic or novel PKCs and atypical PKCs. At least 12 isozymes have been identified in the PKC family. The commonly mentioned eight homologous PKC isozymes are: PKCα, PKCβI, PKCβII, PKCγ, PKCδ, PKCε, PKCθ and PKCη. [25] The rest four are novel isozymes (PKCδ, PKCε, PKCθ and PKCη).

The phospholipid diacylglycerol (DAG) plays a central role in the activation of PKC by causing an increase in the affinity of PKCs for cell membranes which is accompanied by PKC activation and pseudo-substrate release. [26] Phorbol ester is oil derived from the seeds of the plant Crotontiglium. It is a more potent activator for PKCs than DAG, producing cellular actions in nanomolar concentrations. [27] Activated PKC then phosphorylates and activates a range of kinases. Signals that stimulate G-protein-coupled receptors, receptor tyrosine kinases and non-receptor protein tyrosine kinases can all cause the production of DAG. [26],[28] The difference between the conventional (PKCα, PKCβI, PKCβII and PKCγ) and novel PKC isoforms is that the former require both DAG and calcium for an activation, while the latter can be activated by DAG alone. Cellular calcium levels are elevated along with DAG levels, because the latter is often co-produced with inositol-1, 4, 5-trisphosphate (Ins (1, 4, 5) P3), which triggers calcium release into the cytosol from internal stores. [4] Moreover, several PKC isotypes are activated independently in a redundant manner through the phospholipase C and phosphatidylinositol 3-kinase pathway. [26]

The downstream events following PKC activation are little known. The main pathway, which is activated by PKC, is the MEK-ERK pathway. The mitogen-activated protein kinase (MAPK) signaling pathways involve a family of PKs that play critical roles in regulation of diverse cellular activities, including cell proliferation, survival, differentiation, motility, and angiogenesis. The MAPK pathways transducer signals from various extracellular stimuli (growth factors, hormones, cytokines and environmental stresses), leading to distinct intracellular responses through a series of phosphorylation events and protein-protein interactions. [29] Four distinct MAPK cascades have been identified and named according to their MAPK module. These are extracellular signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase, p38 and ERK5. Each of these cascades comprised of three sequentially acting kinases, activating one after the other (MAPKKK/MAP3K, MAPKK/MAP2K, and MAPK). MAP2K or MAPKK are commonly known as MEK proteins. MEK1 and MEK2 are the prototype members of MEK family proteins. Several MEK inhibitors are in clinical trials. Selumetinib has been studied in combination with docetaxel in phase II randomized trial in previously treated patients with advanced lung cancer. [30]


 > The Diverse Roles of PKCS In Modulating Cancer Top


Increased levels of PKC have been associated with malignant transformation in a number of cell lines including breast, [31] lung [32] and gastric carcinomas. [33]

The 12 isozymes have distinct and in some cases opposing roles in cell growth and differentiation. [34],[35],[36],[37] Although PKCβ, PKCε, and PKCy are targets in phorbol ester-mediated tumor promotion/progression, PKCδ is tumor-suppressive. For example, PKCδ activation increases angiogenesis in human prostate cancer cells, [38] PKCε overexpression is observed in stomach, lung, thyroid, colon and breast cancers, [39] PKCη has been implicated in NSCLC in which increased levels of PKCη correlate with tumor aggressiveness and cell proliferation levels [40],[41] and PKCθ overexpression has been associated with gastrointestinal stromal tumours. PKCα has a significant role in cellular proliferation [42] and PKCβ in vasculogenesis (PKCβ), [43] the two processes that are essential for cancer growth and metastasis.

PKCα

PKCα has long been recognized to have a role in regulating aspects of tumor growth and development. [44] Its most consistent function is the regulation of cell motility. PKCα activation results in increased cell motility in several in vivo and in vitro cancer models, the effect of which may be reversed on PKCα inhibition. [45] However, yet this role is highly tissue-dependent because in some cases, it acts as a tumor promoter and in others it functions as a tumor suppressor. Overexpression of PKCα has been demonstrated in tissue samples of prostate, endometrial, high-grade urinary bladder and hepatocellular cancers, [46] while for hematological malignancies up- or down-regulation of PKCα has been described and in basal cell carcinoma and colon cancers, down-regulation of PKCα has been observed. [47] A mixed picture also pertains to breast cancer cells, where it has been studied extensively. Whereas, activation or over-expression of PKCα has been shown in breast cancer cells and in breast tumor samples by some, [48] down-regulation has been demonstrated by others. [49] Selective targeting of PKCα therefore has potential therapeutic value in a wide variety of disease states, although will be technically complicated by the ubiquitous expression and multiple functions of the molecule.

PKCβ

PKCβ have been studied extensively for its role in lung cancer therapies, especially its impact against NSCLC. One of the PKCβ inhibitor-enzastaurin has been used in combined therapies treating NSCLC. Enzastaurin is a biological targeted agent actively being investigated against different tumors as a single agent or in combination. The mechanism of Enzastaurin is resulting in G2/M-checkpoint abrogation, favoring apoptosis induction in pemetrexed-damaged cells. However, not all the downstream events following PKCβ inhibition by enzastaurin are completely known. [50]

The difficulty lies in the development of the assays to evaluate possible biomarkers, such as the expression of PKC, vascular endothelial growth factor and Glycogen synthase kinase 3 beta (GSK3β), in tissues and/or in blood samples. Moreover, the interactions between the widely expressed PKCβ and other forms of PKCs add to the complexity: Similar as PKCα, tissue and cell specificity should also be noted in applying PKCβ-related treatments. However different from PKCα, it should be considered quite consistent that inhibition of PKCβ brings apoptosis, thus leading to shrinkage of tumors.

PKCθ

One of the obstacles in developing effective anti-cancer therapies is the acquired resistance for apoptosis among many cancer cell lines. PKCθ, which is expressed relatively selectively in T cells, plays an important role in mature T cell activation and proliferation upon its translocation to the plasma membrane. Studies have shown that PKCθ provides an important survival signal that protects leukemic T cells from Fas- or UV-induced apoptosis. [51] Thus, much effort has been exerted to the study of PKCθ leukemic T cell survival and/or proliferation.

It has been tested of the role of PKCθ in T cell leukemia progression by inducing this disease in wild-type (wt) and PKCθ-deficient mice with moloney-murine leukemia virus (M-MuLV). [52] Under comparable conditions, disease incidence was higher and disease onset more rapid in PKCθ (-/-) mice. Transfer of leukemic T cells from wt donors into PKCθ-deficient and wt recipients induced leukemia in 100% and 40% of the mice, respectively. Interestingly, leukemic cells from PKCθ (-/-) donors induced the disease in only 50% of the PKCθ-deficient and 10% of the wt recipients. These results suggested a more careful examination of the chronic treatment of humans with PKCθ inhibitors because PKCθ might play an essential role for the immune response to leukemia.

It is to be argued that in this study, there might be complementary regulations by other PKCs because it is well-accepted that PKCs have inter-linked functions. Whether or not it is attributed to PKCθ alone and how much the immune response in leukemia is accounted on PKCθ remain to be investigated.

PKCε

The localization of PKCε in numerous tissues and its importance in key cellular pathways raises the possibility of many therapeutic strategies based on the inhibition of this isozyme. Cells over-expressing PKCε form tumors in nude mice with an incidence rate of 100%.

PKCε shows the greatest oncogenic potential of the PKC family. [53] Contribution of PKCε to carcinogenesis depends on the Ras/Raf/MAP kinase cascade, which is a well examined pathway of intracellular signal transmission. Activation of the Ras/Raf/MAP kinase cascade results in the transcription of genes involved in cell proliferation and growth. Over-expression of PKCε was shown to increase Akt (a family of serine/threonine kinases) protein levels and activation, which is essential for the anti-apoptotic effects of numerous Akt phosphorylated substrates, including caspase-9 and forkhead transcription factors. Furthermore, an indirect regulation of Akt by PKCε was observed through interactions with integrins and/or the secretion of growth factors. [54]

Successful recognition of PKCε as a cancer marker and a target for selective drugs may only be a question of time, due to new discoveries in tumor biology and pharmaceutical advances. There is considerable hope for nanomaterials as efficacious carriers of apoptosis inducers and/or selective signal transduction blockers.

PKCη

The PKCη gene resides at chromosome 3q26 and is a frequent target of tumor-specific gene amplification in multiple forms of human cancer. PKCη gene amplification in turn drives PKCη over-expression in these cancers. Genetic disruption of PKCη expression blocks multiple aspects of the transformed phenotype of human cancer cells including transformed growth in soft agar, invasion through matrigel and growth of subcutaneous tumors in nude mice.

The signaling pathway for PKCη activation involves Rac1, MEK, ERK. [55] The transforming activity of PKCη requires the N-terminal PB1 (Phox-Bem1) domain of PKCη, which serves to couple PKCη with downstream effector molecules. Novel cancer therapeutics is developed to target at the PB1 domain. The compounds aurothioglucose and aurothiomalate screened to disrupt the PB1 domain is currently in Phase I clinical trials for the treatment of NSCLC.

PKCδ

PKCδ is among the most expressed PKC isozymes. Both the full-length and the catalytic fragment of PKCδ may translocate to distinct cellular compartments, including mitochondria and the nucleus, to reach their targets. Overexpression of PKCδ stimulates apoptosis in a wide variety of cell types through a mechanism that is incompletely understood. [56] PKCδ-deficient cells are impaired in their response to DNA damage-induced apoptosis, suggesting that PKCδ is required for an apoptotic response to stress.

How PKCδ influences apoptosis is largely remained to be understood. Ghayur et al. showed that the expression of the catalytic fragment of PKCδ in HeLa cells was sufficient to induce cell death, [57] thus establishing a direct link between PKCδ and apoptosis.

Mizuno et al. also showed that transfection of catalytically active full-length PKCδ also resulted in apoptotic morphology. [58] It was speculated that an increase in kinase activity of PKCδ may cause apoptosis and that the production of a PKCδ catalytic fragment during apoptosis may not be a byproduct, but one of the key participants during late stages of apoptosis. A recent report also suggested that apoptosis induced by PKCδ was independent of its kinase activity since wild-type and dominant-negative PKCδ had equivalent effects on apoptosis. [59]


 > Future Directions Top


In this review, we have discussed the three most common pathological causes for lung cancer, and the PKC family as one of the most important targets in developing potential therapies.

The presence of PKC isoforms with differential activation and tissue distribution [60] raised the possibility of developing PKC isozyme-specific inhibitors with the potential for targeting specific intracellular pathways. Many strategies have been used to investigate PKCs in lung injury, especially lung cancer. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. [61],[62] More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. [36],[63],[64] To define the isozymes to be targeted can be quite difficult as it is complex to describe individual effect without interactions. Besides identifying the individual PKCs activated in lung tissue or isolated cells in response to an environmental injury can be difficult. Traditionally, isozyme activation is detected by measuring intracellular translocation to membrane or cytoskeleton. Translocation to membrane can be detected by Western blotting, measurement of catalytic activity following subcellular fractionation, or immunostaining with confocal imaging of intact cells. Sensitivity of these assays is dependent on antibody affinity. Immunoprecipitation/kinase assays are also used to evaluate the activity of individual PKC isozymes. [65] The phosphorylation state of PKCs is a critical determinant of activity. [66],[67]

Although extensive efforts are required for a further elucidation of individual functions, on the other hand, it might be useful to look into the paired interactions. It is clearly observed that various PKCs isoforms couple with each other and function in synergy or in complementary, such as the tumor cell metastasis regulation exerted by PKCα and PKCε, as well as their synergic neuronal functions in various neuron degenerative diseases. The advantages of studying PKC functions as pairs are (1) to enable developing effective therapies before a detailed understanding of interaction mechanisms. (2) To effectively amplify therapeutic functions by synergic and complementary regulations. (3) To circumvent the difficulty in isolating individual PKC isoforms. Yet, this is not to deny that the study of individual mechanisms of the various PKCs is necessary. PKCs is a center of several intracellular signaling pathways, an improved understanding of their functions facilitate the development of therapies for many other diseases besides cancer.

Moreover, the recently highlighted therapeutic target of micro ribonucleic acid (miRNA) also offers a potential combination with PKCs to develop effective strategies. There is accumulating evidence that specific miRNAs correlated with drug sensitivity in NSCLC. [68] However, a greater knowledge of miRNAs might also provide novel insights in several drug-resistance mechanisms. [69] Hence, it is suggested that a combination treatment of miRNAs and PKCs is a potential therapeutic strategy, by sensitizing tumor cells to drug-induced apoptosis as well as by inhibiting tumor proliferation and invasive capabilities.

Lung cancer has the highest death toll among all kinds of cancers. There are varied treatments for the disease except for the chemo and radio-therapies. The newly discovered molecular targets as well as prognosis strategies are promising and guiding our current progress in treating cancers toward a more effective and less toxic landscape. Inhibitors of various PKC isoforms have been synthesized and applied in combination with chemo-and radio-therapies to improve therapy effectiveness and repress side-effects. PKCs, due to its various isoforms and its important roles in proliferation, have been extensively targeted for cancer research. As more evidence collected, a better understanding of PKC family renders a range of potential anti-cancer therapies.

 
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