MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC

Ma, Jun; Zhao, Zhihui; Wu, Kaiming; Xu, Zhe; Liu, Kuanzhi

doi:10.1016/j.gene.2016.04.054

Cited by 27 publications

(26 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mitochondrial apoptosis induction is the mechanism by which cisplatin plays the anti-tumor effect [34]. Our results indicated that miR-125a-dependent inhibition of HAX-1 promoted cisplatin to damage the mitochondria of Hep-2-CSCs.…”

Section: Discussionmentioning

confidence: 78%

Inhibition ofHAX-1by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells

Tang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

Chemoresistance is a major obstacle in chemotherapy of laryngeal carcinoma. Recently, studies indicate that cancer stem cells are responsible for chemotherapy failure. In addition, microRNAs play important roles in tumor initiation, development and multidrug resistance. In the present study, we found that the expression of microRNA-125a was decreased in laryngeal carcinoma tissues and Hep-2 laryngeal cancer stem cells (Hep-2-CSCs). MicroRNA-125a gain-of-function significantly increased the sensitivity of Hep-2-CSCs to cisplatin in vitro and in vivo. Combination with microRNA-125a mimics can decrease the half maximal inhibitory concentration of Hep-2-CSCs to cisplatin. Mechanically, we found that microRNA-125a reverses cisplatin resistance in Hep-2-CSCs by targeting Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1). Inhibition of HAX-1 by microRNA-125a significantly promotes the cisplatin-induced apoptosis in Hep-2-CSCs through mitochondrial pathway. In addition, multidrug resistance of Hep-2-CSCs to vincristine, etoposide and doxorubicin was greatly improved after the cells were transfected with microRNA-125a mimics. These dates strongly suggested the promotion of microRNA-125a/HAX-1 axis on chemotherapy of laryngeal carcinoma.

show abstract

Section: Discussionmentioning

confidence: 78%

Inhibition ofHAX-1by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells

Tang

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…Myeloid cell leukemia sequence 1 is a FBXW7 substrate that is associated with CDDP resistance in several types of malignancy . To determine whether MCL1 is regulated by FBXW7 in CC cells treated with CDDP, we analyzed MCL1 levels in FBXW7‐depleted CC cells by immunoblotting.…”

Section: Resultsmentioning

confidence: 99%

“…The current standard for chemotherapy in advanced and recurrent CC is the combination of GEM and CDDP, but its efficacy is limited due to the development of chemoresistance, the mechanisms of which are not well understood. Several studies have, however, described the relationship between CDDP resistance and the accumulation of MCL1 . Unlike other B‐cell lymphoma two family members, MCL1 is unstable and provides a mechanism for cells to shift from survival to apoptosis in response to stressors .…”

Section: Discussionmentioning

confidence: 99%

“…Cholangiocarcinoma cells are resistant to chemotherapeutic agents such as CDDP, accounting for the poor prognosis of CC . Several studies have described the relationship between the mechanism of CDDP resistance and the accumulation of MCL1 . Despite the importance of MCL1 in several cancers, the relationship between the FBXW7/MCL1 pathway and CDDP‐induced apoptosis in CC has not been previously investigated, and the association between FBXW7 and MCL1 in CC remains unknown.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

et al. 2018

View full text Add to dashboard Cite

The ubiquitin ligase F‐box and WD repeat domain‐containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease‐free and overall survival were significantly worse in the low‐FBXW7 group than in the high‐FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease‐free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self‐renewal. Interestingly, when cells were stimulated with cis‐diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7‐mediated ubiquitylation is context‐dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1.

show abstract

“…Among the first-line chemotherapeutic agents for a wide variety of solid tumors, cisplatin (CisPt) kills tumor cells by forming DNA adducts that lead to DNA damage by activating the apoptotic program; however, it is capable of inducing chemoresistance(Kartalou & Essigmann, 2001). Some BH3-mimetics compounds (among which is obatoclax) act as Bcl-2 inhibitors by binding to the BH3 grooves on the surfaces of antiapoptotic family members(Bodur & Basaga, 2012) by activating the proapoptotic proteins and promoting apoptosis Ma, Zhao, Wu, Xu, and Liu (2016). investigated the value of the Pan-Bcl-2 inhibitor as a sensitizer for the chemotherapy of CisPt-resistant NSCLC cells.They found that obatoclax decreased the IC 50 of CisPt in CisPt-resistant NSCLC cells and that the obatoclax-promoted cell death induced by CisPt was dependent on the inhibition of MCL-1 that is the target of obatoclax.…”

mentioning

confidence: 99%

Mcl‐1 targeting could be an intriguing perspective to cure cancer

Blasio

Vento

Fiore

2018

Journal Cellular Physiology

View full text Add to dashboard Cite

The Bcl-2 family, which plays important roles in controlling cancer development, is divided into antiapoptotic and proapoptotic members. The change in the balance between these members governs the life and death of the cells. Mcl-1 is an antiapoptotic member of this family and its distribution in normal and cancerous tissues strongly differs from that of Bcl-2. In human cancers, where upregulation of antiapoptotic proteins is common, Mcl-1 expression is regulated independent of Bcl-2 and its inhibition promotes senescence, a major barrier to tumorigenesis. Cancer chemotherapy determines various kinds of responses, such as senescence and autophagy; however, the ideal response to chemotherapy is apoptosis. Mcl-1 is a potent oncogene that is regulated at the transcriptional, posttranscriptional, and posttranslational levels. Mcl-1 is a short-lived protein that, in the NH2 terminal region, contains sites for posttranslational regulation that can lead to proteasomal degradation. The USP9X Mcl-1 deubiquitinase regulates Mcl-1 and the levels of these two proteins are strongly correlated. Mcl-1 has three splicing variants (the antiapoptotic protein Mcl-1L and the proapoptotic proteins Mcl-1S and Mcl-1ES), each contributing toward apoptosis regulation. In cancers responsible for the most deaths in the world, the presence of Mcl-1 is associated with malignant cell growth and evasion of apoptosis. Mcl-1 is also one of the key regulators of cancer stem cells' self-renewal that contributes to tumor survival. A great number of indirect and selective Mcl-1 inhibitors have been produced and some of these have shown efficacy in several clinical trials. Thus, therapeutic manipulation of Mcl-1 can be a useful strategy to combat cancer.

show abstract

MCL-1 is the key target of adjuvant chemotherapy to reverse the cisplatin-resistance in NSCLC

Cited by 27 publications

References 39 publications

Inhibition ofHAX-1by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells

Inhibition ofHAX-1by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells

FBXW7 modulates malignant potential and cisplatin‐induced apoptosis in cholangiocarcinoma through NOTCH1 and MCL1

Mcl‐1 targeting could be an intriguing perspective to cure cancer

Contact Info

Product

Resources

About