A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells

Rasmussen, Megan L.; Kline, Leigh A.; Park, Kyungho P.; Ortolano, Natalya A.; Romero-Morales, Alejandra I.; Anthony, Christin C.; Beckermann, Kathryn E.; Gama, Vivian

doi:10.1016/j.stemcr.2018.01.005

Cited by 56 publications

(75 citation statements)

References 35 publications

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“…[139][140][141] Changes in the dynamic mitochondrial network can also influence the identity, self-renewal capacity and commitment of stem cells, which reinforces the functional connection between morphology and metabolism, and which likely has implications for cancer (stem) cells as well. [142][143][144][145] Similar changes in the mitochondrial morphology have been observed also in T lymphocytes upon activation. Memory T cells on the other hand are quiescent, depend on oxidative phosphorylation, and hence showed a more fused morphology.…”

Section: Determinants Of the Mitochondrial Network Morphologysupporting

confidence: 72%

“…Interestingly, cancer cells and stem cells share the same energy metabolism and hence share a similar mitochondrial morphology . Changes in the dynamic mitochondrial network can also influence the identity, self‐renewal capacity and commitment of stem cells, which reinforces the functional connection between morphology and metabolism, and which likely has implications for cancer (stem) cells as well . Similar changes in the mitochondrial morphology have been observed also in T lymphocytes upon activation.…”

Section: Mitochondrial Membrane Organizationmentioning

confidence: 63%

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Targeted OMA1 therapies for cancer

Alavi¹

2019

Intl Journal of Cancer

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The mitochondrial inner membrane proteins OMA1 and OPA1 belong to the BAX/BAK1‐dependent apoptotic signaling pathway, which can be regulated by tumor protein p53 and the prohibitins PHB and PHB2 in the context of neoplastic disease. For the most part these proteins have been studied separate from each other. Here, I argue that the OMA1 mechanism of action represents the missing link between p53 and cytochrome c release. The mitochondrial fusion protein OPA1 is cleaved by OMA1 in a stress‐dependent manner generating S‐OPA1. Excessive S‐OPA1 can facilitate outer membrane permeabilization upon BAX/BAK1 activation through its membrane shaping properties. p53 helps outer membrane permeabilization in a 2‐step process. First, cytosolic p53 activates BAX/BAK1 at the mitochondrial surface. Then, in a second step, p53 binds to prohibitin thereby releasing the restraint on OMA1. This activates OMA1, which cleaves OPA1 and promotes cytochrome c release. Clearly, OMA1 and OPA1 are not root causes for cancer. Yet many cancer cells rely on this pathway for survival, which can explain why loss of p53 function promotes tumor growth and confers resistance to chemotherapies.

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Section: Determinants Of the Mitochondrial Network Morphologysupporting

confidence: 72%

Section: Mitochondrial Membrane Organizationmentioning

confidence: 63%

Targeted OMA1 therapies for cancer

Alavi¹

2019

Intl Journal of Cancer

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“…MCL-1 encodes an anti-apoptotic protein that is a member of the Bcl-2 family [27]. Two research teams, those of Kelly, G. L and Gasca, J, reported that MCL-1 and other Bcl-2 family proteins were altered in response to chemotherapy [28][29]. MCL-1 and WNT/β-catenin were both listed as potential therapeutic target genes in liver cancer [30].…”

Section: Discussionmentioning

confidence: 99%

MCL-1 plays an oncogenic role in breast cancer by modulating chemoresistance and stemness properties by activating Wnt/β-catenin

Zhang

Zhu

Zhang

et al. 2020

Preprint

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Background Breast cancer is the most common malignant tumor and the leading cause of death in women. Chemotherapy is one of the most important treatments for breast cancer. However, the development of chemotherapy resistance is the main cause of 20–30% of breast cancer patients developing metastasis, leading to death. MCL-1, an anti-apoptotic protein, has not been found to contribute to chemotherapy resistance in breast cancer. Methods We used large gene panels to detect pathological sections of tumors in drug-resistant and sensitive patients. We validated protein profiling by IHC in a larger cohort of samples. We performed the function of MCL-1 by knockdown and overexpression in vitro and in vivo. Luciferase assay and CHIP assay were used to prove the regulatory network between MCL-1 and LRP6. Result We found that MCL-1 is more highly expressed in drug-resistant breast cancer tissues than it is in sensitive breast cancer tissues. Functional studies have revealed that MCL-1 plays an important role in drug resistance by regulating apoptosis in breast cancer cells. We found that overexpression of MCL-1 enhances the chemoresistance and stemness of breast cancer cells in vitro and in vivo, while silencing has the opposite effect. Mechanistically, by downregulating and upregulating MCL-1, we show that MCL-1 regulates LRP6 and activates the WNT/β-catenin signaling pathway in breast cancer cells. Finally, we found that a high level of MCL-1 expression predicts a poor prognosis in breast cancer. Conclusion Our work highlights the role of MCL-1 in chemoresistance and stemness. The MCL-1-WNT/β-catenin axis might be used as a new clinical target for breast cancer therapy.

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“…The functional role of MCL1 in cancer stemness other than leukemia yet has been less investigated. Recent studies showed that MCL-1 can reside at the mitochondrial matrix in pluripotent stem cells, and regulate the pluripotency through mitochondrial dynamics (44). Furthermore, MCL1 is highly expressed in embryonic stem cells (ESCs), and Inhibition of MCL1 selectively kills ESC and induced-pluripotent stem cells (45, 46).…”

Section: Discussionmentioning

confidence: 99%

Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

Lin

Hsu

et al. 2018

Preprint

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Lung cancer is the leading cause of cancer-associated death worldwide. Early metastasis and the recurrence remain major challenges for lung cancer treatment in clinic. Targeting the cancer stemness could be a potential strategy to restrain tumor progression. In the current study, we found that in lung adenocarcinoma (LAC), BMI1 and MCL1 play crucial roles in invasion, chemo-resistance, and tumor initiation. JNK signaling is a link between oncogenic pathway or environment stress to cancer stemness. The activation of JNK, either by EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3-ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small-molecule BI-44 was synthesized, which effectively suppressed BMI1/MCL1 expression and inhibited tumor formation and progression in preclinical models. Targeting BMI1/MCL1 provides the basis for a new therapeutic approach in the treatment of LAC.

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A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells

Cited by 56 publications

References 35 publications

Targeted OMA1 therapies for cancer

Targeted OMA1 therapies for cancer

MCL-1 plays an oncogenic role in breast cancer by modulating chemoresistance and stemness properties by activating Wnt/β-catenin

Targeting BMI1 and MCL1 for Lung Adenocarcinoma Treatment

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