Nf kb and cancer how intimate is this relationship really over

nf kb and cancer how intimate is this relationship really over

gene in B cells, research on NF-kB continues to yield new insights into fundamental aberrant activation has been associated: cancer, autoim- unlikely that IkBa and IkBb are truly interchangeable. Indeed .. the IkBR gene suggests no relationship to the IkB family Rel/NF-kB/IkB family: Intimate tales of association. tumors. Thus, inhibiting NF-κB signaling has potential therapeutic . Actually, the p50 and p52 proteins have no intrinsic those transduced through LTβR, potentiate NF-κB dimer activation in a NIK dependent .. Prasad, S.; Ravindran, J .; Aggarwal, B.B. NF-κB and cancer: How intimate is this relationship. In this review, we summarize how studies on the role of NF-κB in different mouse leads to liver cancer, TNF has a crucial role in preserving liver homeostasis. . Whether recruitment of FADD and activation of caspase-8 really occur at fates of death or survival are intimately linked by NF-κB activation.

This may never be proven conclusively in our lifetime, but the connections are so incredibly close that it is difficult to deny the relationship. Several diseases that are defined by chronic inflammation result in significantly increased risks of cancer, such as colon cancer in patients with ulcerative colitis an inflammatory bowel disease. Also, many of the inflammatory conditions that often lead to cancer include auto-immune diseases the body attacking itself which we know is one of the results of chronic stress and inflammation.

Other scientific data quote one in five cancers results from inflammation, and extrapolating from the studies on stressit would not be unreasonable to assume this would include stress-induced inflammation. Another more common example is cigarette smoke, which causes chronic inflammation in the lungs, producing oxidation and free-radicals and leads to DNA damage and chronic obstructive pulmonary disease as well as lung cancer.

These inflammatory cytokines have also been shown to cause cancer to spread metastasize to other organs,9 result in further inflammation, and even cause tumors to increase their blood supply angiogenesis.

When reviewing all the data it appears likely that the answer is both are true. Epidemiologic data, acknowledging all of its shortcomings, has revealed that chronic inflammation correlates with tumor progression in patients already with cancer.

nf kb and cancer how intimate is this relationship really over

Epidemiologic data has shown that chronic depression, stress, and lack of social support are all risk factors for cancer. Just like the mice that had an increase in their inflammatory cytokines from social stress in the last post, another study took mice prone to skin cancer and gave them artificial sun exposure for 10 weeks.

Half of the mice were chronically stressed and half were not. The chronically stressed mice had decreased immune function and experienced tumor development significantly earlier than the non-stressed mice.

Interestingly and conversely, studies show that mindfulness meditation, a form of stress alleviation, actually stimulates the immune system, resulting in increased ability to fight viral pathogens, and potentially fight cancer. Cortisol causes the level of glucose in the blood to rise, and if this occurs too frequently, could lead to chronically elevated levels of blood glucose a state similar to diabetes, which in itself may lead to cancer20, In fact, stress can raise blood glucose levels to double their normal amount Depression, a common form of chronic stress, causes hyperactive responses to stress and a chronically elevated levels of cortisol, which undoubtedly will lead to a chronically elevated level of blood sugar.

Chronic stress works counter to this goal and any way to minimize it would be beneficial.

There was a problem providing the content you requested

Similar to the mouse study above, another group looked at skin tumors squamous cell carcinoma in a group of mice prone to such cancers, to see if acute stress could modify this.

One group of mice was restrained for 2. Each PCR assay was performed in triplicates on at least three separate biological replicates. We have previously shown that Pax-5 expression levels inversely correlate with those from FAK in cancer cells [ 22 ]. We thus set out to establish the effects of Pax-5 overexpression on FAK expression and phosphorylation levels active form. In addition, Pax-5 transfected cells also displayed attenuated phosphorylated forms of FAK.

Control samples were also performed which include Pax-5 recombinant expression and GAPDH as an internal loading control.

These results strongly suggest that Pax-5 is a modulator of FAK expression and activation in breast cancer cells. We thus made use of the MCF7 breast cancer cell model transfected with Pax-5 and evaluated the expression levels of: As expected, we found that the expression levels from the majority of signaling components located downstream of FAK were attenuated by Pax On the other hand, Pax-5 completely abrogated the levels of p38, phosphorylated JNK, and paxillin.

We were unable to detect any PI3K levels in our cell models data not shown. Altogether, our results further support a role for Pax-5 as a repressor of the FAK-induced signaling cascade in breast cancer cells.

nf kb and cancer how intimate is this relationship really over

The presented data is the calculated mean of three independent samples and is representative of three different experiments. Click on the image to enlarge. To elucidate the regulatory mechanisms of Paxmediated suppression of FAK expression, we examined the capacity of Pax-5 to regulate FAK gene transcription in breast cancer cells.

Surprisingly, no significant differences in FAK transcript levels were observed between Pax-5 or vector-transfected cells Figure 2 A. We found that Pax-5 transfected cells only displayed a mild decrease in FAK reporter activities figure 2 B.

NF-kappaB and cancer: how intimate is this relationship.

To assess the role of Pax-5 in FAK protein stabilization, we examined the expression levels of Src, phosphorylated Src and calpain, two known regulators of FAK protein stability [ 4445 ]. Pax-5 regulates FAK modulators Given that FAK transcriptional control was very moderate following Pax-5 transfection, we expanded our studies to examine the potential of Pax-5 to affect other commonly known regulators of FAK gene expression.

Figure 2 Paxmodulates FAK protein levels by indirect mechanisms. The presented data is the calculated mean and representative of three different experiments in relation to the non-transfected parental cell line. B FAK promoter transactivation potential was assessed using dual reporter gene assays Promega with the FAK promoter region cloned upstream from the firefly luciferase gene [ 41 ].

Can Excess Stress Cause Cancer?

Normalization of luciferase activity was performed using non-inducible renilla luciferase and plotted in relative light units RLU to each respective control sample. Results are representative of triplicate experiments. These results suggest that p53 is an important modulator of Paxinduced suppression of FAK in breast cancer cells.

We found that Pax-5 induced miRb expression levels 5 fold in comparison to vector transfected controls Figure 3 D. Pax-5 regulates aggressiveness of breast cancer through FAK We have previously shown that the expression levels of Pax-5 pro-epithelial and FAK pro-mesenchymal inversely correlate during breast cancer progression.

To determine whether Pax-5 suppresses breast cancer invasiveness through the mediated inhibition of FAK, we conducted several rescue experiments using conditional expression of both Pax-5 and FAK on breast cancer migration properties.

First, we evaluated cell migration in the epithelial-dominant MCF7 cell line which were knocked-down for Pax-5 endogenous expression using a pool of siRNAs siPax-5 in addition to concomitantly inhibiting FAK using the FAK-specific chemical inhibitor As expected, control treatments which consisted of untouched cells; scrambled siRNA transfection; and FAK inhibitor treated cells did not migrate Figure 4 A.

More importantly, the observed induction of migration in Pax-5 attenuated cells was completely abolished when FAK was inhibited by chemical treatment Figure 4 A. These findings suggest that the induction of cell migration in Pax-5 downregulated cells is FAK dependant. To confirm our observations, we also studied cell migration in mesenchymal-dominant BT cells stably transfected with either the Pax-5 gene BTPax5 or the empty vector alone as a control BTCT.

Overall, our results suggest that Pax-5 mediated suppression of breast cancer cell migration is dependent of FAK activity. Discussion Breast cancer metastasis is a multistep process, which consists of a cancer cell acquiring new biological processes and transitioning between phenotypic identities EMT-MET to colonize new environments. We and others have recently reported that the expression of Pax-5 in cancer cells suppresses mesenchymal properties and concomitantly promotes epithelial features reminiscent of MET [ 212235 ].

Moreover, we have shown that the expression levels of pro-epithelial factor Pax-5 inversely correlate with those from pro-malignant FAK in cancer cells [ 22 ] thus suggesting a molecular relationship between these genes which could lead to the modulation of EMT-MET processes.

nf kb and cancer how intimate is this relationship really over

In this study, we demonstrate that Pax-5 acts as a potent inhibitor of FAK expression and activity leading to the concomitant suppression of aggressive features in breast cancer cells. Normalization of firefly luciferase activity was performed using non-inducible renilla luciferase and plotted in relative light units RLU to each respective control.

Figure 4 Paxmediated suppression of breast cancer migration is FAK dependent. Results are the calculated mean of raw fluorescence and representative of triplicate experiments. In an attempt to elucidate the molecular mechanisms supporting Paxmediated suppression of FAK, we first assessed the potential of the Pax-5 transcription factor to modulate FAK gene expression.

These observations thus suggested that the FAK gene promoter is targeted for Pax-5 binding and transactivation data not shown. Surprisingly, despite the significant downregulation of FAK protein levels by Pax-5, we were unable to detect any significant changes in neither FAK transcriptional levels; nor FAK reporter gene activity following Pax-5 conditional expression in the breast cancer model tested.

We extended our study to examine the impact of Pax-5 on previously reported modulators of FAK expression. First, we found that Pax-5 induces p53 which has previously been reported in breast cancer cells [ 21 ]. Rescue experiments also validate that p53 may be a prominent means for Pax-5 to inhibit FAK expression.

Indeed, these results concur with reports showing that elevated Pax-5 expression in primary breast tumor sites correlates with lower risk of disease progression and relapse [ 22 ]. Our findings thus strongly support a beneficial role for Pax-5 expression in breast primary tumors.

[email protected]: Eavesdropping on Bacteria

Aberrantly expressed miRNAs are frequently associated with a variety of cancers including breast cancers [ 58 - 60 ]. MiRa has been identified to increase apoptosis and decrease proliferation in classic Hodgkin lymphoma by targeting JAK2 [ 61 ]. Recently, miRb was reported to target FAK resulting in the suppression of cancer cell invasion [ 46 ]. In our study, we found that Pax-5 induced miRb expression in breast cancer cells which would again increase Pax-5's capacity to downregulate FAK protein expression and suppress breast cancer progression.

nf kb and cancer how intimate is this relationship really over

Altogether, our study describes a new role for Pax-5 as a FAK inhibitor and tumor suppressor of breast cancer processes. Mechanistically, we demonstrate that Pax-5 inhibits FAK expression and activation indirectly through the regulation of FAK modulators notably through p These findings are striking given that Pax-5 is a potent oncogene in lymphoid cancers [ 63 ]. The study herein suggests that Paxmediated suppression of breast cancer aggressiveness is largely due to FAK inhibition.

These finding are of particular interest given the association of FAK in invasive cancers and the interest in FAK targeting as a promising anticancer strategy [ 6465 ]. Conflict of interest We have no potential conflicts of interest to disclose. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. The role of focal-adhesion kinase in cancer - a new therapeutic opportunity.

Focal adhesion kinase and cancer. Zhao J, Guan JL. Signal transduction by focal adhesion kinase in cancer. Journal of cellular physiology. JNK phosphorylates paxillin and regulates cell migration. Combinatorial activation of FAK and AKT by transforming growth factor-beta1 confers an anoikis-resistant phenotype to myofibroblasts.

Luo M, Guan JL. Overexpression of focal adhesion kinase in head and neck squamous cell carcinoma is independent of fak gene copy number.

nf kb and cancer how intimate is this relationship really over

Expression of tyrosine kinases FAK and Pyk2 in human astrocytomas. Novel protein kinases expressed in human breast cancer. Immunohistochemical analyses of focal adhesion kinase expression in benign and malignant human breast and colon tissues: High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype.

Increased expression of focal adhesion kinase in thyroid cancer: J Korean Med Sci. Focal adhesion kinase is required for bombesin-induced prostate cancer cell motility. Overexpression of focal adhesion kinase in primary colorectal carcinomas and colorectal liver metastases: Bailey KM, Liu J.

Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. Breast Cancer Res Treat.