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CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation.

ABSTRACT: mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (cancerous inhibitor of PP2A [protein phosphatase 2A]) as a key modulator of mTORC1 and autophagy. CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhancing mTORC1-dependent growth signaling and inhibiting autophagy. This regulatory circuit is reversed by ubiquitination and p62/SQSTM1-dependent autophagic degradation of CIP2A and subsequent inhibition of mTORC1 activity. Consistent with CIP2A's reported ability to protect c-Myc against proteasome-mediated degradation, autophagic degradation of CIP2A upon mTORC1 inhibition leads to destabilization of c-Myc. These data characterize CIP2A as a distinct regulator of mTORC1 and reveals mTORC1-dependent control of CIP2A degradation as a mechanism that links mTORC1 activity with c-Myc stability to coordinate cellular metabolism, growth, and proliferation.

SUBMITTER: Puustinen P

PROVIDER: S-EPMC3941044 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation.

Puustinen Pietri P Rytter Anna A Mortensen Monika M Kohonen Pekka P Moreira José M JM Jäättelä Marja M

The Journal of cell biology 20140301 5

mTORC1 (mammalian target of rapamycin complex 1) integrates information regarding availability of nutrients and energy to coordinate protein synthesis and autophagy. Using ribonucleic acid interference screens for autophagy-regulating phosphatases in human breast cancer cells, we identify CIP2A (cancerous inhibitor of PP2A [protein phosphatase 2A]) as a key modulator of mTORC1 and autophagy. CIP2A associates with mTORC1 and acts as an allosteric inhibitor of mTORC1-associated PP2A, thereby enhan ...[more]

PMID: 24590173

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Project description:T‑cell acute lymphoblastic leukemia (T‑ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T‑cell progenitors. Conventional treatments for T‑ALL fail to prevent or cure the disease, with a high‑risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T‑ALL. Niclosamide, a traditional oral anti‑helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T‑ALL. Here, the present study aimed to investigate the anti‑leukemia effects of niclosamide on T‑ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T‑ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T‑ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T‑ALL cells treated with niclosamide, changes in apoptosis‑ and autophagy‑related proteins were analyzed by western blotting. In addition, in an in vivo model, T‑ALL xenograft mice were used to study the anti‑leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF‑CEM T‑ALL cells in both a dose‑ and time‑dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF‑CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase‑3 and LC3B, while downregulated those of Bcl‑2 and p62, in a dose‑dependent manner in both Jurkat and CCRF‑CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T‑ALL xenograft mice by activating cleaved caspase‑3 and LC3B. We conclude that niclosamide plays an anti‑leukemia role, and that it represents a novel approach for the treatment of T‑ALL.

Dataset Information

CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation.

Publications

CIP2A oncoprotein controls cell growth and autophagy through mTORC1 activation.

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