Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells

Ren, Hui; Guo, Hua; Thakur, Asmitananda; Zhang, Shuo; Wang, Ting; Liang, Yiqian; Shi, Pengpeng; Gao, Lei; Liu, Feng; Feng, Jing; Chen, Tianjun; Tian, Yang; Shang, Dong; Liu, JJ; Xu, Feng; Chen, Mingwei

doi:10.18632/oncotarget.11645

Cited by 20 publications

(8 citation statements)

References 35 publications

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“…However, we observed that the combined treatment of a suboptimal dose of metformin enhanced the effects of chloroquine on the suppression of growth in all three pancreatic cell lines examined. Likewise blockade of MEK inhibitor induced autophagy has been shown to sensitize certain cancer cells to the PI3K/AKT inhibitor NVP-BKM120 (Ren et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Metformin influences drug sensitivity in pancreatic cancer cells

Candido

Abrams

Steelman

et al. 2018

Advances in Biological Regulation

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Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic malignancy and accounts for 85% of pancreatic cancers. PDAC patients have poor prognosis with a five-year survival of only 5-10% after diagnosis and treatment. Pancreatic cancer has been associated with type II diabetes as the frequency of recently diagnosed diabetics that develop pancreatic cancer within a 10-year period of initial diagnosis of diabetes in increased in comparison to non-diabetic patients. Metformin is a very frequently prescribed drug used to treat type II diabetes. Metformin acts in part by stimulating AMP-kinase (AMPK) and results in the suppression of mTORC1 activity and the induction of autophagy. In the following studies, we have examined the effects of metformin in the presence of various chemotherapeutic drugs, signal transduction inhibitors and natural products on the growth of three different PDAC lines. Metformin, by itself, was not effective at suppressing growth of the pancreatic cancer cell lines at concentration less than 1000 nM, however, in certain PDAC lines, a suboptimal dose of metformin (250 nM) potentiated the effects of various chemotherapeutic drugs used to treat pancreatic cancer (e.g., gemcitabine, cisplatin, 5-fluorouracil) and other cancer types (e.g., doxorubicin, docetaxel). Furthermore, metformin could increase anti-proliferative effects of mTORC1 and PI3K/mTOR inhibitors as well as natural products such as berberine and the anti-malarial drug chloroquine in certain PDAC lines. Thus, metformin can enhance the effects of certain drugs and signal transduction inhibitors which are used to treat pancreatic and various other cancers.

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Section: Discussionmentioning

confidence: 99%

Metformin influences drug sensitivity in pancreatic cancer cells

Candido

Abrams

Steelman

et al. 2018

Advances in Biological Regulation

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“…NVP-BKM-120 induces ERK activation and autophagy. Suppression of ERK activation resulted in increased therapeutic effectiveness against the lung cancer cells [ 120 ]. The effectiveness of PD0325901 has been examined in cells which proliferate in response to mutant HRAS and was determined to be effective in suppressing growth, especially in combination with mTOR inhibitors [ 121 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

Abrams

Ruvolo

et al. 2017

Oncotarget

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A critical problem in leukemia as well as other cancer therapies is the development of chemotherapeutic drug-resistance. We have developed models of hematopoietic drug resistance that are based on expression of dominant-negative TP53 [TP53 (DN)] or constitutively-active MEK1 [MEK1(CA)] oncogenes in the presence of chemotherapeutic drugs. In human cancer, functional TP53 activity is often lost in human cancers. Also, activation of the Raf/MEK/ERK pathway frequently occurs due to mutations/amplification of upstream components of this and other interacting pathways. FL5.12 is an interleukin-3 (IL−3) dependent hematopoietic cell line that is sensitive to doxorubicin (a.k.a Adriamycin). FL/Doxo is a derivative cell line that was isolated by culturing the parental FL5.12 cells in doxorubicin for prolonged periods of time. FL/Doxo + TP53 (DN) and FL/Doxo + MEK1 (CA) are FL/Doxo derivate cell lines that were infected with retrovirus encoding TP53 (DN) or MEK1 (CA) and are more resistant to doxorubicin than FL/Doxo cells. This panel of cell lines displayed differences in the sensitivity to inhibitors that suppress mTORC1, BCL2/BCLXL, MEK1 or MDM2 activities, as well as, the proteasomal inhibitor MG132. The expression of key genes involved in cell growth and drug-resistance (e.g., MDM2, MDR1, BAX) also varied in these cells. Thus, we can begin to understand some of the key genes that are involved in the resistance of hematopoietic cells to chemotherapeutic drugs and targeted therapeutics.

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“…A number of studies have suggested that increased extracellular signal-regulated kinase (ERK) phosphorylation levels induce autophagy in cells ( 12 , 13 ), and that SphK1 promotes the proliferation of colon cancer cells through activation of the ERK/phosphorylated (p-)ERK cascade ( 14 ). In the present study, the hypothesis that the activation of the SphK1/ERK/p-ERK pathway promotes autophagy in HT-29 cells was examined.…”

Section: Introductionmentioning

confidence: 99%

Activation of the SphK1/ERK/p‑ERK pathway promotes autophagy in colon cancer cells

Zhang

Liu

et al. 2018

Oncol Lett

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Sphingosine kinase 1 (SphK1) is a master kinase that catalyzes the synthesis of sphingosine 1 phosphate and participates in the regulation of cell proliferation and autophagy. The present study aimed to assess the effects of the activation of the SphK1/extracellular signal-regulated kinase (ERK)/phosphorylated (p-)ERK pathway in the regulation of autophagy in colon cancer (HT-29) cells. Inverted fluorescence microscopy was used to detect the expression of green fluorescent protein (GFP) in the SphK1-overexpressing HT-29 cells [SphK1(+)-HT-29] and the negative control HT-29 cells (NC-HT-29). Western blotting was used to detect the protein expression levels of SphK1, ERK1/2, p-ERK1/2, as well as those of the autophagy-associated markers LC3A, ATG5, and ULK1. Protein localization and expression of the LC3A antibody were detected by immunofluorescence. The results demonstrated that GFP was similarly expressed in SphK1(+)-HT-29 and NC-HT-29 cells. However, significantly increased SphK1 mRNA and protein expression levels were detected in SphK1(+)-HT-29 cells compared with in NC-HT-29 cells, which resulted in upregulated ERK/p-ERK. Furthermore, the protein expression levels of the three autophagy-associated markers increased. LC3A protein was localized in the cytoplasm of SphK1(+)-HT-29 cells, indicating autophagy. In summary, the findings of the present study suggested that activation of the SphK1/ERK/p-ERK pathway promotes autophagy in colon cancer HT-29 cells.

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Blockade efficacy of MEK/ERK-dependent autophagy enhances PI3K/Akt inhibitor NVP-BKM120's therapeutic effectiveness in lung cancer cells

Cited by 20 publications

References 35 publications

Metformin influences drug sensitivity in pancreatic cancer cells

Metformin influences drug sensitivity in pancreatic cancer cells

Targeting signaling and apoptotic pathways involved in chemotherapeutic drug-resistance of hematopoietic cells

Activation of the SphK1/ERK/p‑ERK pathway promotes autophagy in colon cancer cells

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