Oncogenic Ras Sensitizes Cells to Apoptosis by Par-4

Nalca, Aysegul; Qiu, Shirley; El-Guendy, Nadia; Krishnan, Sumathi; Rangnekar, Vivek M.

doi:10.1074/jbc.274.42.29976

Cited by 98 publications

(86 citation statements)

References 32 publications

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“…In this context, it is important that NF-kB is a key antiapoptotic factor (Barkett and Gilmore, 1999), and activation of ras in combination with NF-kB blockage resulted in an increased level of apoptosis in certain cells (Mayo et al, 1997(Mayo et al, , 2001Nalca et al, 1999). Surprisingly, in our experiments, we found only a modest increase in apoptosis in keratinocytes in the upper granular layer of K5-GR+/ras+ tumors in comparison with w.t./ras+ tumors.…”

Section: Discussioncontrasting

confidence: 55%

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

et al. 2003

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y These authors contributed equally to the work Glucocorticoids are effective inhibitors of epidermal proliferation and skin tumorigenesis. Glucocorticoids affect cellular functions via glucocorticoid receptor (GR), a well-known transcription factor. Recently, we generated skin-targeted transgenic mice overexpressing GR under control of the keratin5 promoter (K5-GR mice). To test the hypothesis that GR plays a role as a tumor suppressor in skin, we bred K5-GR transgenic mice with Tg.AC transgenic mice, which express v-Ha-ras oncogene in the skin, and compared the susceptibility of F1 offspring to TPA-induced skin carcinogenesis. GR overexpression in the epidermis dramatically inhibited skin tumor development. In K5-GR/ras+ double transgenic mice papillomas developed later and the average number of tumors per animal was 15% (in males) and 40% (in females) of the number seen in wild type (w.t./ras+) littermates. In addition, the papillomas in w.t./ras+ animals were eight to nine times larger. GR overexpression resulted in a decrease in keratinocyte proliferation combined with a modest increase in apoptosis and differentiation of keratinocytes in K5-GR/ras+ papillomas. Our data clearly indicate that interference of GR transgenic protein with nuclear factor kappa B (NF-jB) transcription factor had resulted in NF-jB blockage in K5-GR/ras+ tumors. We discuss the role of NF-jB blockage in tumor-suppressor effect of GR.

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Section: Discussioncontrasting

confidence: 55%

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

et al. 2003

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“…In addition, oncogenic ras is a potent down-regulator of pro-apoptotic and growth inhibitory signaling genes such as par-4 (Nalca et al, 1999) and TGF-b signaling cascade (Saha et al, 2001). Thus, mutations in K-ras P-RT -PCR analysis of dnmt1.…”

Section: Discussionmentioning

confidence: 99%

Farnesyltransferase inhibitor (L-744,832) restores TGF-β type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2

et al. 2002

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Activated ras is known to dysregulate TGF-b signaling by altering the expression of TGF-b type II receptor (RII). It is well documented that tumor cells harboring mutant ras are more resistant to radiation than cells with wild-type ras. In this study, we hypothesized that the use of farnesyltransferase inhibitor (FTI,832) may directly restore TGF-b signaling through RII expression via ras dependent or independent pathway leading to induction of radiation sensitivity. Two pancreatic cancer cell lines, BxPC-3 and MIA PaCa-2 were used in this study. FTI inhibited farnesylation of Ras protein more significantly in MIA PaCa-2 than BxPC-3 cells. In contrast, MIA PaCa-2 cells were resistant to radiation when compared to BxPC-3 cells. BxPC-3 cells were more resistant to FTI than MIA PaCa-2 cells. In combination treatment, no significant radiosensitizing effect of FTI was observed in BxPC-3 cells at 5 or 10 mM. However, in MIA PaCa-2 cells, a significant radiosensitizing effect was observed at both 5 and 10 mM concentrations (P40.004). The TGF-b effector gene p21 waf1/cip1 was elevated in combination treatment in MIA PaCa-2 but not in BxPC-3 cells. In MIA PaCa-2 cells, FTI induced TGF-b responsive promoter activity as assessed by 3TP-luciferase activity. A further induction of luciferase activity was observed in MIA PaCa-2 cells treated with radiation and FTI. Induction of TGF-b signaling by FTI was mediated through restoration of the RII expression, as demonstrated by RT -PCR analysis. In addition, re-expression of RII by FTI was associated with a decrease in DNA methyltransferase 1 (DNMT1) levels. Thus, these findings suggest that the L-744,832 treatment restores the RII expression through inhibition of DNMT1 levels causing induction of TGF-b signaling by radiation and this forms a novel molecular mechanism of radiosensitization by FTI.

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“…7). Since the proapoptotic protein PAWR regulates endogenous BCL2 in prostate cancer cells, 39 therefore, whole cell lysates of GFP and GFP-PAWR-overexpressing cells were employed for coimmunoprecipitation. Of interest, the results showed less expression of BECN1 and BCL2 proteins in the input of GFP-PAWR overexpressing cells but not in GFP transfected cells suggesting a regulatory role of PAWR over BECN1 expression.…”

Section: The 3-awa-induced Autophagy To Apoptosis Switching Is Mediatmentioning

confidence: 99%

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

Rah¹,

Rasool²,

Nayak³

et al. 2015

Autophagy

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Oncogenic Ras Sensitizes Cells to Apoptosis by Par-4

Cited by 98 publications

References 32 publications

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

Glucocorticoid receptor functions as a potent suppressor of mouse skin carcinogenesis

Farnesyltransferase inhibitor (L-744,832) restores TGF-β type II receptor expression and enhances radiation sensitivity in K-ras mutant pancreatic cancer cell line MIA PaCa-2

PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells

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