Forskolin increases the effect of everolimus on aromatase inhibitor-resistant breast cancer cells

Abstract

Aromatase inhibitor (AI) resistance is a major obstacle in the treatment of estrogen receptor-positive breast cancer. Everolimus (EVE) ameliorates AI-resistant breast cancer and is therefore used in cancer treatment. However, some patients show resistance to EVE. Here, we used 30 clones of long-term estrogen-deprived (LTED) MCF-7 cells as a model of AI-resistant breast cancer. We examined changes in protein phosphatase type 2A (PP2A) and cancerous inhibitor of PP2A (CIP2A), a negative regulator of PP2A, in LTED cells treated with EVE. In LTED cells with high sensitivity to EVE, CIP2A expression decreased at low EVE concentrations; however, in LTED cells poorly sensitive to EVE, CIP2A and PP2A did not change upon exposure to EVE. Therefore, we hypothesized that there is a relation between expression of CIP2A and sensitivity to EVE. Knockdown of CIP2A increased the sensitivity to EVE in three clones poorly sensitive to EVE. Additionally, we found that treatment with FSK, which activates PP2A, increased the sensitivity of the cells to EVE. Our data point to CIP2A and PP2A as novel therapeutic targets for AI-resistant breast cancer.

The Therapeutic Potential of the Labdane Diterpenoid Forskolin

“…Recent studies suggest that forskolin can increase the antitumoral effects of some anticancer drugs [74,78,79]. In this regard, the treatment with forskolin increased the sensitivity of Aromatase inhibitor-breast cancer cells to everolimus [78] and human triple negative breast cancer cells to doxorubicine [79] through activating PP2A and a mechanism dependent on the cAMP/PKA mediated extracellular-signal-regulated kinase (ERK) inhibition, respectively (Figure 3). Moreover, reports from several other animal studies are available online [74].…”

“…Perrotti and Neviani reviewed that forskolin activates protein phosphatase-2A (PP2A) and antagonize leukemogenesis in multiple solid tumors (both in vitro and in vivo) [77]. Recent studies suggest that forskolin can increase the antitumoral effects of some anticancer drugs [74,78,79]. In this regard, the treatment with forskolin increased the sensitivity of Aromatase inhibitor-breast cancer cells to everolimus [78] and human triple negative breast cancer cells to doxorubicine [79] through activating PP2A and a mechanism dependent on the cAMP/PKA mediated extracellular-signal-regulated kinase (ERK) inhibition, respectively (Figure 3).…”

Upregulation of CIP2A in estrogen depletion‐resistant breast cancer cells treated with low‐dose everolimus

“…We previously established 30 clones of LTED cells and performed drug sensitivity assays to determine the half-maximal inhibitory concentration (IC 50 ) for EVE in each clone [18,19]. To further evaluate the effect of EVE on CIP2A mRNA expression, we selected three LTED clones (DC-cells: clone number L3, L5, and L22) highly responsive to EVE and three clones (IC-cells: clone number L4, L7, and L29) poorly responsive to EVE.…”

“…Our previous studies showed that the proliferative capacity of Highly responsive EVE LTED clones (DC‐cells) was suppressed at low concentrations of EVE (IC 50 < 1.5 n m ), whereas that of Poorly responsive EVE LTED clones (IC‐cells) was not affected even at high EVE concentrations (IC 50 > 200 n m ) [19]. In this study, we investigated whether low concentrations EVE (0.01 n m ) affect the proliferation of three strains of LTED cells in which CIP2A was increased (increased CIP2A cells: IC‐cells) and three strains in which CIP2A was decreased (decreased CIP2A cells: DC‐cells).…”

<p>Forskolin exerts anticancer roles in non-Hodgkin&rsquo;s lymphomas via regulating Axin/&beta;-catenin signaling pathway</p>

“…Its analog 8-CPT-cAMP [8-(4-chlorophenylthio) adenosine 3′, 5′-cyclic monophosphate] has been documented to promote apoptosis of lymphoma cells 13. Importantly, forskolin, the cAMP-elevating agent, exerts anticancer roles in many kinds of cancers, and also improves the chemosensitivity of conventional drugs 14–16. However, the effects of forskolin in NHL remain unclarified.…”