Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Paillas, Salomé; Boissière, Florence; Bibeau, Frédéric; Denouël, Amélie; Mollévi, Caroline; Causse, Annick; Denis, Vincent; Vezzio-Vié, Nadia; Marzi, Laetitia; Cortijo, Cédric; Aït-Arsa, Imade; Askari, Nadav; Pourquier, Philippe; Martineau, Pierre; Rio, Maguy Del; Gongora, Céline

doi:10.1158/0008-5472.can-10-2726

Cited by 75 publications

(78 citation statements)

References 36 publications

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“…16,17,47,48 Here we show that downregulation of p38MAPK activity by attenuation of its isomerisation either by mutation of Pro224 or by knock down of CypA leads to higher sensitivity to cisplatin. This combinatory effect of cisplatin with aberrantly activated p38MAPK was demonstrated in several cell lines (Figure 6), as well as with a mouse model of lung tumorigenesis (Figures 7e-g).…”

Section: Discussionmentioning

confidence: 61%

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

et al. 2016

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The stress-induced p38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in multiple physiological processes, including cancer. In turn, p38MAPK phosphorylation at Thr180 and Tyr182 is a key regulatory mechanism for its activation and functions. Here we show that this mechanism is actively regulated through isomerisation of Pro224. Different cyclophilins can isomerise this proline residue and modulate the ability of upstream kinases to phosphorylate Thr180 and Tyr182. In vivo mutation of Pro224 to Ile in endogenous p38MAPK significantly reduced its phosphorylation and activity. This resulted in attenuation of p38MAPK signalling, which in turn caused an enhanced apoptosis and sensitivity to a DNA-damaging drug, cisplatin. We further found a reduction in size and number of lesions in homozygous mice carrying the p38MAPK P224I substitution in a K-ras model of lung tumorigenesis. We propose that cyclophilin-dependent isomerisation of p38MAPK is an important novel mechanism in regulating p38MAPK phosphorylation and functions. Thus, inhibition of this process, including with drugs that are in clinical trials, may improve the efficacy of current anti-cancer therapeutic regimes.

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Section: Discussionmentioning

confidence: 61%

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

et al. 2016

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“…These cell lines have been obtained in 2000, were amplified and frozen, and one aliquot of each was thawed for this project, although no authentication was done by the authors. The SN-38-resistant HCT116 and SW48 cell clones were obtained as previously described (7,9,12). Briefly, the reference SN-38-sensitive HCT116 cell clone (HCT116-s) was exposed to 10 nmol/L SN-38 and cloned to obtain the HCT116-SN6 and HCT116-A2 clones.…”

Section: Cell Linesmentioning

confidence: 99%

“…Cell-growth inhibition and cell viability after SN-38 treatment were assessed using the sulforhodamine B (SRB) assay (9). Exponentially growing cells were seeded in 96-well plates (1,000 cells/well) in RPMI-1640 supplemented with 10% FCS.…”

Section: Drug-sensitivity Assaymentioning

confidence: 99%

“…To this aim, we used SN-38-resistant HCT116 (Table 2) and SW48 clones (9). The sorafenib IC 50 in SN-38-resistant HCT116 clones were between 2.2 mmol/L (HCT116-SN6 clone) and 3.45 mmol/L (HCT116-G7 clone; Fig.…”

Section: Sorafenib Associated With Sn-38 Reverses Chemoresistance In mentioning

confidence: 99%

“…Like other camptothecin derivatives, SN-38 is an inhibitor of topoisomerase I, a nuclear enzyme needed for replication and transcription through relaxation of supercoiled DNA (4,5). Cellular mechanisms causing irinotecan/SN-38 resistance have been reported for each step of the CPT-11 pathway (6)(7)(8)(9). Among them, it has been shown that cultured cells that are resistant to camptothecin derivatives have reduced intracellular drug accumulation, mediated by the ATPbinding cassette (ABC) transporter ABCG2 (10), especially in colon cancer cells (11,12).…”

Section: Introductionmentioning

confidence: 99%

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Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

Mazard

Causse

Simony

et al. 2013

Molecular Cancer Therapeutics

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Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. We used both in vitro (the HCT116, SW48, SW620, and HT29 colon adenocarcinoma cell lines and four SN-38-resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38-resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan or its active metabolite, SN-38. We have shown that sorafenib improved the antitumoral activity of irinotecan in vitro, in both parental and SN-38-resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecanmediated p38 and ERK activation. In conclusion, our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in CRC, particularly in KRAS-mutated tumors.

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Apoptosis Induced by Benzyl Isothiocyanate in Gefitinib-Resistant Lung Cancer Cells is Associated with Akt/MAPK Pathways and Generation of Reactive Oxygen Species

Liu

Yan

et al. 2012

Cell Biochem Biophys

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Gefitinib is the first targeted drug approved for non-small cell lung cancer (NSCLC) treatment. Clinical trails showed that patients with certain clinical and histologic characteristics (such as women, patients of East Asian descent, no history of smoking, and adenocarcinoma) had higher rates of response and overall survival. Despite excellent clinical response to gefitinib in certain NSCLC patients, nearly all patients who respond initially to gefitinib later develop drug resistance. Isothiocyanates have been shown to possess antitumor activity, inhibiting several types of cancer cells growth. However, there are limited studies on their effects on chemoresistance of cancer cells. In this report, we found that benzyl isothiocyanate (BITC) inhibited gefitinib-resistant human NSCLC cells growth by inducing apoptosis in a dose-dependent manner, and activated caspase-3. There were no effects of BITC on epidermal growth factor receptor and multidrug resistant proteins expression. BITC caused cell cycle arrest at G2/M phase, reactive oxygen species generation, and glutathione depletion. Akt activity and NFκB transcriptional activation were suppressed; mitogen-activated protein kinase and activator protein 1 (AP-1) were activated. Our results demonstrated that BITC overcame gefitinib resistance in lung cancer cells. The further understanding of the anti-resistance mechanism of BITC would contribute to establish it as a potent lead compound for the synthesis of novel anticancer drugs.

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Targeting the p38 MAPK Pathway Inhibits Irinotecan Resistance in Colon Adenocarcinoma

Cited by 75 publications

References 36 publications

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

Proline isomerisation as a novel regulatory mechanism for p38MAPK activation and functions

Sorafenib Overcomes Irinotecan Resistance in Colorectal Cancer by Inhibiting the ABCG2 Drug-Efflux Pump

Apoptosis Induced by Benzyl Isothiocyanate in Gefitinib-Resistant Lung Cancer Cells is Associated with Akt/MAPK Pathways and Generation of Reactive Oxygen Species

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