Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-κB inhibition

Cheng, Qingwen; Lee, Ho H.; Liu, Ying; Parks, Thomas P.; Cheng, Genhong

doi:10.1038/sj.onc.1203861

Cited by 96 publications

(65 citation statements)

References 21 publications

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“…NF-B has been shown to regulate apoptosis through induction of antiapoptotic proteins such as Bcl-2 homologue A1/Bf1, the immediate-early-response gene IEX-1L, the inhibitors of apoptosis c-IAP1 and c-IAP2, TRAF1, TRAF2 and Mn-SOD. [21][22][23][24] Moreover, inhibition of the NF-B activity in THP-1 cells were starved overnight in 2% FCS and were then incubated with 1 g/ml LPS for 12 min before whole-cell lysates were prepared and subjected to immunoprecipitation using an IKK antibody. CHS 828 at different concentrations was added to the activated isolated IKK and incubated for 30 min at 30°C.…”

Section: Discussionmentioning

confidence: 99%

“…36 Many chemotherapeutic agents have been shown to induce NF-B activity during the treatment, which led to an induction of antiapoptotic proteins, thereby decreasing the sensitivity of the cancer cells toward the treatment. 9,21,23,25,[37][38][39][40][41][42][43][44][45][46][47] Therefore, a combination of chemotherapeutic treatment and inhibition of the NF-B activity could be beneficial for the patient. In line with this, mice bearing HT-1080 tumors expressing the superrepressor form of I B␣ exhibited an increased sensitivity toward treatment with the chemotherapeutic compound camptothecin.…”

Section: Discussionmentioning

confidence: 99%

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Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Olsen

Hjarnaa

Latini

et al. 2004

Intl Journal of Cancer

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Olsen

Hjarnaa

Latini

et al. 2004

Intl Journal of Cancer

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“…In cell-lines, Bfl-1 overexpression protected cells from treatment with cisplatin 395 , etoposide 59 , and staurosporin (STS) 396 . Fortunately, knocking down Bfl-1 expression re-sensitised malignant B-cells to chemotherapy 385 .…”

Section: The Role Of Bfl-1 In Cancermentioning

confidence: 99%

“…In these cells, over-expression is thought to tip the balance between the pro-survival and pro-apoptotic members of the Bcl-2 family in favour of cell survival. For this reason, Bfl-1 has been theorised to lend to the intrinsic resistance to chemotherapy seen in many of the cancers where it is over-expressed 395 .…”

Section: Introductionmentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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“…In addition, P388/VFL resistant cells exhibited a higher relative level of Bfl-1/A1 expression, another Bcl-2 family anti-apoptotic member (Zhang et al, 2000), which appears to play a role in the apoptotic response of tumour cells to chemotherapy, having been shown to inhibit etoposide-induced apoptosis (Wang et al, 1999a). Furthermore, expression of Bfl-1/A1 in NF-kappaB deficient cells provided protection against etoposide and cisplatin treatment (Cheng et al, 2000). Our data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.…”

Section: A -P388 Cellsmentioning

confidence: 98%

Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development

et al. 2002

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Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms.

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Upregulation of Bcl-x and Bfl-1 as a potential mechanism of chemoresistance, which can be overcome by NF-κB inhibition

Cited by 96 publications

References 21 publications

Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Anticancer agent CHS 828 suppresses nuclear factor‐κB activity in cancer cells through downregulation of IKK activity

Role of the pro-survival molecule Bfl-1 in melanoma

Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development

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