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Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.

ABSTRACT: The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity.

SUBMITTER: Folgiero V

PROVIDER: S-EPMC3542615 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.

Folgiero V V Di Carlo S E SE Bon G G Spugnini E P EP Di Benedetto A A Germoni S S Pia Gentileschi M M Accardo A A Milella M M Morelli G G Bossi G G Mottolese M M Falcioni R R

Cell death & disease 20121206

The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activi ...[more]

PMID: 23222510

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Project description:Bronchopulmonary neuroendocrine tumours (BP-NETs) comprise a large spectrum of tumours including typical carcinoids (TCs), atypical carcinoids (ACs), large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) that exhibit considerably different biological aggressiveness and clinical behaviours. The phosphatidylinositol-3-kinase α catalytic subunit (PIK3CA) gene is known to be involved in the pathogenesis of several types of human cancers through gene amplification, deletions or somatic missense mutations within the helical and catalytic domains. However, the PIK3CA gene status in BP-NETs has yet to be explored. This study aimed to investigate the PIK3CA gene status in a large series of BP-NETs by direct gene sequencing and to analyse its correlation with the main clinicopathological parameters. To the best of our knowledge, we demonstrated for the first time a high frequency of somatic missense mutations (23.2%) in the PIK3CA gene in a series of 190 BP-NETs, including 75 TCs, 23 ACs, 17 LCNECs and 75 SCLCs. The frequency of the PIK3CA gene mutation in the kinase domain was higher (17.9%) than that in the helical domain (5.3%). When the mutational status of the PIK3CA gene was compared with the main clinical and pathological characteristics of the BP-NET patients, we found a significant association between PIK3CA gene mutations and BP-NET histology (p=0.011). Interestingly, the frequency of PIK3CA gene mutations increased with the biological aggressiveness of all BP-NETs, except LCNECs. In conclusion, our results suggest that PIK3CA gene mutations may play a key role in tumourigenesis and aggressiveness of BP-NETs. The PIK3CA gene may represent a favourable candidate for an effective therapeutic strategy in the treatment of patients with BP-NETs.

Dataset Information

Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.

Publications

Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.

Similar Datasets

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