Morphological changes and nuclear translocation of DLC1 tumor suppressor protein precede apoptosis in human non-small cell lung carcinoma cells

Yuan, Bao‐Zhu; Jefferson, Amy M.; Millecchia, Lyndell; Popescu, Nicholas C.; Reynolds, Steven H.

doi:10.1016/j.yexcr.2007.08.009

Cited by 45 publications

(58 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, when we examined the correlation between cytoplasmic and nuclear DLC1, and their combined effects on patients' 5-year survival, we found that for metastatic melanoma patients, concurrent loss of both forms (category 1) was associated with the worst survival outcome, whereas loss of either cytoplasmic or nuclear DLC1 (categories 2 and 3) was associated with an intermediate survival outcome (Figure 4). This could imply that, similar to what has been reported in non-small cell lung carcinomas, 34 the tumor suppressor properties of cytoplasmic and nuclear DLC1 differ from one another in melanoma. Thus, simultaneous loss of cytoplasmic and nuclear DLC1 could confer additive or synergistic effects on cancer progression, metastasis, and patient survival.…”

Section: Discussionsupporting

confidence: 75%

“…34 In 2008, Scholz et al 35 showed that DLC1 was continuously shuttled between the cytoplasm and nuclei in cell lines, and yet another study from 2011 by Chan et al 36 confirmed these results and further showed that DLC1 localized to the focal adhesions did not partake in the shuttling, and that nuclear DLC1 was less efficient in exerting its tumor suppressor activities compared with cytoplasmic DLC1. Whether or not this is also the case in melanoma remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival

et al. 2014

View full text Add to dashboard Cite

Deleted in Liver Cancer-1 (DLC1) is a Rho-GTPase-activating protein known to be downregulated and function as a tumor suppressor in numerous solid and hematological cancers. Its expression status in melanoma is currently unknown however, prompting us to examine this. Using immunohistochemistry and tissue microarrays containing a large set of melanocytic lesions (n ¼ 539), we examined the expression profile of DLC1 in melanoma progression, as well as the association between DLC1 and patient survival. We detected both cytoplasmic and nuclear DLC1 expression, and found that whereas cytoplasmic DLC1 was significantly downregulated in metastatic melanoma compared with nevi and primary melanoma, nuclear DLC1 expression was significantly down in primary melanoma compared with nevi, and then further down in metastatic melanoma. Loss of cytoplasmic DLC1 was significantly associated with poorer overall and disease-specific 5-year survival rates of all melanoma (Po0.001 and P ¼ 0.001, respectively) and metastatic melanoma patients (P ¼ 0.020 and 0.008, respectively), and similar results were seen for nuclear DLC1 (Po0.001 for both overall and disease-specific survival for all melanoma patients, and P ¼ 0.004 for metastatic melanoma patients). Next, we examined the correlation between cytoplasmic and nuclear DLC1 and found that concomitant loss of both forms was associated with the worst outcome for metastatic melanoma patients (P ¼ 0.013 and P ¼ 0.008 for overall and disease-specific 5-year survival, respectively). Finally, multivariate Cox regression analysis determined that strong cytoplasmic and nuclear DLC1 expression was a favorable independent prognostic factor for all melanoma (HR, 0.61; 95% CI, 0.42-0.88; P ¼ 0.008) and metastatic melanoma patients (HR, 0.42; 95% CI, 0.23-0.77; P ¼ 0.005). Although more research still needs to be done on the topic, these preliminary results support the hypothesis that DLC1 is a tumor suppressor in melanoma. Modern Pathology (2014Pathology ( ) 27, 1203Pathology ( -1211 doi:10.1038/modpathol.2013 published online 21 February 2014 Keywords: DLC1; immunohistochemistry; melanoma; metastasis; rhogap; tissue microarray; tumor suppressorThe incidence of cutaneous melanoma has been steadily increasing in the non-Hispanic White population worldwide since the 1950s. 1 In the United States, incidence rates have increased by an average 2.8% per annum since 1992 in nonHispanic Whites, currently making it the fifth and seventh most commonly diagnosed cancer in men and women, respectively. 2 Although melanoma accounts for less than 5% of all skin cancers, it is responsible for over 80% of all skin cancer-related deaths. 2 These numbers are greatly attributable to the high metastatic potential of melanoma, and are reflected by a 5-year survival rate of only 5-16% for patients with distant metastases compared with a rate well above 90% for patients with early-stage, localized melanoma. [2][3][4][5] Rho-GTPases belong to the small GTPase family of proteins, and are commonly implicated in the progr...

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Activation of caspases has a central role in apoptosis, and DLC1-mediated inhibition of liver, ovarian or lung cancer cell proliferation was previously shown to be associated with the induction of apoptosis mediated by caspase-3. [18][19][20] Consistent with these previous observations, infection with Ad-DLC1 induced an approximately 2.5-fold increase in caspase-3 activity in C4-2-B2 cells (Figure 3b).…”

Section: Induction Of Apoptosis By Dlc1supporting

confidence: 90%

Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

et al. 2008

View full text Add to dashboard Cite

Our recent study showing highly recurrent loss of function of DLC1 (deleted in liver cancer 1), a tumor suppressor gene in primary prostate carcinoma (PCA), implicates this gene in the pathogenesis of this disease. To evaluate the response of PCA to oncosuppressive activity of DLC1, we examined now the effects of adenoviral vector for human DLC1 transduction into the DLC1-deficient, androgen-independent (AI) and aggressive human PCA cell lines PC-3 and C4-2-B2. Adenovirus-mediated restoration of DLC1 expression inhibited the proliferation, invasiveness and anchorage-independent growth of PC-3 and C4-2-B2 cells in vitro as well as the tumorigenicity of PC-3 cells in nude mice. It also induced cell-cycle arrest, inhibited the activation of RhoA and the formation of actin stress fibers. DLC1 induced apoptosis in C4-2-B2 cells, whereas it did not elicit such an effect in PC-3 cells. The abundance of the antiapoptotic protein Bcl-2 was greater in PC-3 cells than in C4-2-B2 cells, and PC-3 cells were rendered sensitive to DLC1-induced apoptosis by treatment with the Bcl-2 inhibitor HA14-1. These results suggest that adenovirus-mediated DLC1 transfer, alone or together with other agents, such as inhibitors of Bcl-2 or histone deacetylase, might prove effective in the treatment of aggressive, AI-PCA.

show abstract

“…(3) Mitochondrial release of the proapoptotic proteins: a previously described procedure was followed to isolate and analyze the cytosol cyto c, Smac and AIF portions (Fiskum et al, 1980). (4) AIF protein nuclear translocation: a previously described procedure for fluorescent immunohistochemical staining was followed to stain the AIF protein in MG132-treated cells (Yuan et al, 2007).…”

Section: Protein Analysesmentioning

confidence: 99%

“…A Mcl-1 cDNA encoding the truncated Mcl-1 S from residue 146, immediately after the TSTD caspase 3 cleavage site (Weng et al, 2005), to the C-terminal end, was amplified by RT-PCR from NCI-H1703 cells with a FLAG tag at its 5 0 end and cloned in pcDNA3.1Zeo( þ ) vector under a cytomegalovirus promoter. Procedures for stable gene transfection described previously were followed (Yuan et al, 2007). Cells resistant against Zeocin (50 ng/ml) were tested for PI-induced apoptosis.…”

Section: Constructs and Gene Transfectionmentioning

confidence: 99%

Proteasome inhibitors induce apoptosis in human lung cancer cells through a positive feedback mechanism and the subsequent Mcl-1 protein cleavage

Chapman

2009

Oncogene

View full text Add to dashboard Cite

Proteasome inhibitors (PIs) are promising new therapeutic agents for treating non-small cell lung carcinoma (NSCLC). To investigate the mechanisms of action of PIs, we analyzed the proapoptotic activities of PIs (MG132 or Bortezomib) in NSCLC cells. We found that both MG132 (>1 lM) and Bortezomib (>0.025 lM) induced a significant apoptosis in NCI-H1703, a PI-sensitive NSCLC cell line, through initially activating the intrinsic apoptosis pathway, leading to the activation of a positive feedback mechanism (PFM), which then conveyed apoptosis signaling from the intrinsic pathway to the extrinsic pathway with formation of a signaling loop for maximal caspase activation. Mcl-1 and Noxa were identified to be the major anti-apoptotic and proapoptotic proteins, respectively, in PI-induced apoptosis and mutually exclusive in protein stability. Although the Mcl-1 protein was upregulated by proteasome inhibition, it was also subjected to caspase 3-dependent cleavage governed by the PFM. Moreover, it was revealed that Mcl-1 protein cleavage contributed to PFM-governed apoptosis in following inter-related ways: reducing the anti-apoptotic Mcl-1; generating the truncated proapoptotic Mcl-1 S ; and inducing a shift of balance between Mcl-1 and Noxa. It was further manifested that tumor necrosis factorrelated apoptosis-inducing ligand boosted MG132's proapoptotic activity through strengthening the PFM in both NCI-H1703 and NCI-H358, a PI-resistant NSCLC cell line. Therefore, this study provides a basis for enhancing the efficacy of PIs in treating NSCLC.

show abstract

Morphological changes and nuclear translocation of DLC1 tumor suppressor protein precede apoptosis in human non-small cell lung carcinoma cells

Cited by 45 publications

References 32 publications

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival

DLC1 expression is reduced in human cutaneous melanoma and correlates with patient survival

Adenovirus-mediated restoration of expression of the tumor suppressor gene DLC1 inhibits the proliferation and tumorigenicity of aggressive, androgen-independent human prostate cancer cell lines: prospects for gene therapy

Proteasome inhibitors induce apoptosis in human lung cancer cells through a positive feedback mechanism and the subsequent Mcl-1 protein cleavage

Contact Info

Product

Resources

About