Molecular characterisation of isogenic taxane resistant cell lines identify novel drivers of drug resistance

Kenicer, J.; Spears, Melanie; Lyttle, Nicola; Taylor, Karen; Liao, Linda M.; Cunningham, C; Lambros, Maryou B.; Mackay, Alan; Yao, Cindy Q.; Reis‐Filho, Jorge S.; Bartlett, John M.S.

doi:10.1186/1471-2407-14-762

Cited by 20 publications

(16 citation statements)

References 23 publications

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“…Along with the overexpression of P-gp ( ABCB1 ), progress in determining other key molecular events that lead to the onset of multiple cross-resistance in PTX-resistant cancers has been greatly hampered [24]. To investigate the degree and mechanism of cross-resistance in PTX-resistant cancer cells, we employed our previously established PTX-resistant sublines, A549-PacR and PC-3-PacR cells, and developed transient cross-resistance to 5-FU, DCT, and CIS (see the Experimental Procedures).…”

Section: Resultsmentioning

confidence: 99%

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

et al. 2016

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Acquired drug resistance is a primary obstacle for effective cancer therapy. The correlation of point mutations in class III β-tubulin (TUBB3) and the prominent overexpression of ATP-binding cassette P-glycoprotein (ABCB1), a multidrug resistance gene, have been protruding mechanisms of resistance to microtubule disruptors such as paclitaxel (PTX) for many cancers. However, the precise underlying mechanism of the rapid onset of cross-resistance to an array of structurally and functionally unrelated drugs in PTX-resistant cancers has been poorly understood. We determined that our established PTX-resistant cancer cells display ABCB1/ABCC1-associated cross-resistance to chemically different drugs such as 5-fluorouracil, docetaxel, and cisplatin. We found that feedback activation of TUBB3 can be triggered through the FOXO3a-dependent regulation of ABCB1, which resulted in the accentuation of induced PTX resistance and encouraged multiplicity in acquired cross-resistance. FOXO3a-directed regulation of P-glycoprotein (P-gp) function suggests that control of ABCB1 involves methylation-dependent activation. Consistently, transcriptional overexpression or downregulation of FOXO3a directs inhibitor-controlled protease-degradation of TUBB3. The functional PI3K/Akt signaling is tightly responsive to FOXO3a activation alongside doxorubicin treatment, which directs FOXO3a arginine hypermethylation. In addition, we found that secretome factors from PTX-resistant cancer cells with acquired cross-resistance support a P-gp-dependent association in multidrug resistance (MDR) development, which assisted the FOXO3a-mediated control of TUBB3 feedback. The direct silencing of TUBB3 reverses induced multiple cross-resistance, reduces drug-resistant tumor mass, and suppresses the impaired microtubule stability status of PTX-resistant cells with transient cross-resistance. These findings highlight the control of the TUBB3 response to ABCB1 genetic suppressors as a mechanism to reverse the profuse development of multidrug resistance in cancer.

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Section: Resultsmentioning

confidence: 99%

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

et al. 2016

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“…The reasons behind development of Tx resistance are many which include changes in expressions of the target molecule, tubulin (βIII tubulin over expression), 22 increase in expressions of drug efflux pumps like MDR-1, changes in expressions of proteins involved in regulation of apoptotic pathways and mitotic checkpoint proteins, 45 and increased ability of the cancer cells to survive under stressed condition with the help of autophagy. 11 There are various studies of characterisation of Tx-resistant cells in different cancer cell lines; 6,46 however, detail time point study of changes in cancer cells in the course of Tx resistance development has not been reported. Since such time point studies of resistance development in patients and animals are out of scope, therefore, understanding in detail the changes that occur in lung cancer cells with time in the way of development of resistance against Tx could help us in better management of the disease and also aid in prevention of resistance development against Tx.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

et al. 2017

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Paclitaxel (Tx) is one of the first-line chemotherapeutic drugs used against lung cancer, but acquired resistance to this drug is a major challenge against successful chemotherapy. In this work, we have focused on the chronological changes of various cellular parameters and associated effect on Tx (10 nM) resistance development in A549 cell line. It was observed, at initial stage, the cell death percentage due to drug treatment had increased up to 20 days, and thereafter, it started declining and became completely resistant by 40 days. Expressions of βIII tubulin and drug efflux pumps also increased over the period of resistance development. Changes in cellular autophagy and reactive oxygen species generation showed a biphasic pattern and increased gradually over the course of upto 20 days, thereafter declined gradually; however, their levels remained higher than untreated cells when resistance was acquired. Increase in extracellular acidification rates and oxygen consumption rates was found to be directly correlated with acquisition of resistance. The depolarisation of mitochondrial membrane potential was also biphasic; first, it increased with increase of cell death up to 20 days, thereafter, it gradually decreased to normal level along with resistance development. Increase in activity of catalase, glutathione peroxidase and glutathione content over these periods may attribute in bringing down the reactive oxygen species levels and normalisation of mitochondrial membrane potential in spite of comparatively higher reactive oxygen species production by the Tx-resistant cells.

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“…Although improvements have been made at the early stage of chemotherapy in breast cancer, a large proportion of patients are non-responsive to current treatment strategies due to drug resistance, such as Paclitaxel [ 14 ], highlighting the necessity to develop strategies to overcome or bypass drug resistance. Because the suppressive role of Bak has been commonly recognized in molecular, cellular, and animal models [ 15 ], it is imperative to illustrate the association between Bak expression and clinical features and therapy strategies.…”

Section: Discussionmentioning

confidence: 99%

High Bak Expression Is Associated with a Favorable Prognosis in Breast Cancer and Sensitizes Breast Cancer Cells to Paclitaxel

Luo

Wang

et al. 2015

PLoS ONE

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Breast cancer has become the leading cause of cancer-related death among women. A large number of patients become resistant to drug chemotherapy. Paclitaxel (Taxol) is an effective chemotherapeutic agent used to treat cancer patients. Taxol has been widely used in human malignancies including breast cancer because it can stabilize microtubules resulting in cell death by causing an arrest during the G2/M phase of the cell cycle. Pro-apoptotic Bcl-2 antagonist killer 1 (Bak) plays an important role in Taxol-induced apoptosis in breast cancer. In our present study, we investigated the expression of the Bak protein and clinicopathological correlations in a large sample of breast cancer tissues by immunohistochemistry. We found that the percentage of high scores of Bak expression in breast cancer was significantly lower than that of the non-cancerous breast control tissue. In addition, lower Bak expression was positively associated with the clinical TNM stage of breast cancer with a significant decrease in overall survival compared with those with higher Bak expression especially in the Luminal and HER2 subtypes. Importantly, higher Bak expression predicted a favorable clinical outcome in the cases treated with Taxol indicated by a higher overall survival than that of patients with lower Bak expression especially in Luminal and HER2 subtypes. Furthermore, these results were confirmed in vitro since overexpression of Bak sensitized breast cancer cells to Taxol by inhibiting proliferation and promoting apoptosis; in contrast, downregulation of Bak through siRNA transfection inhibited Taxol induced-apoptosis. Therefore, our results demonstrate that Bak acts as a sensitive biomarker and favorable prognostic factor for Taxol treatment in breast cancer. The restoration of Bak expression would be therapeutically beneficial for Taxol resistant breast cancer patients.

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Molecular characterisation of isogenic taxane resistant cell lines identify novel drivers of drug resistance

Cited by 20 publications

References 23 publications

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

Multiplicity of acquired cross-resistance in paclitaxel-resistant cancer cells is associated with feedback control of TUBB3 via FOXO3a-mediated ABCB1 regulation

Paclitaxel resistance development is associated with biphasic changes in reactive oxygen species, mitochondrial membrane potential and autophagy with elevated energy production capacity in lung cancer cells: A chronological study

High Bak Expression Is Associated with a Favorable Prognosis in Breast Cancer and Sensitizes Breast Cancer Cells to Paclitaxel

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