Dual Inhibition of Pirarubicin-Induced AKT and ERK Activations by Phenformin Sensitively Suppresses Bladder Cancer Growth.

Mei Peng,Jiahui Long,Xiaoping Yang,Miao Mo,Caimei He,Di Xiao,Sichun Zhou,Nan Zhang,Jun Deng

doi:10.3389/fphar.2019.01159

Abstract

Activations of Akt or ERK pathway induced by clinical drugs promote therapeutic failure due to decrease of drug response, and no available strategies have been developed to solve these problems. In this study, we found that pirarubicin (THP), one important chemotherapeutic drug for treating bladder cancer intravesically, dramatically elevated phosphorylations of both Akt and Erk1/2 in addition to inducing DNA damage. MK2206 or AZD6244, representative Akt and Erk1/2 inhibitors, respectively, profoundly sensitized bladder cancer cells to THP treatment. Interestingly, we found that inhibition of a single arm of either Akt or Erk1/2 pathway would induce the increase of another arm, indicating the existence of the crosstalk between these two pathways. Thus, simultaneous suppression of both signals may be needed for increasing the sensitivity of THP. On the other hand, we revealed that phenformin efficiently inhibited both Akt and Erk1/2 phosphorylation in a dose-dependent manner. Furthermore, we demonstrated that phenformin, mimicking dual inhibitors, plays dramatically synergistic action with THP both in vitro and in vivo. Our findings suggest that combination therapy of THP with dual inhibitors may constitute a successful strategy for improving chemotherapy response.

Highlights

Bladder cancer is one of the most frequent cancers of the urinary tract; it accounted for about 60,490 new cases and 12,240 deaths in the United States in 2017 (Siegel et al, 2017)
To determine whether that pirarubicin (THP) treatment induces alterations of either Akt or/and Erk1/2 phosphorylation, the levels of Akt and Erk1/2 phosphorylation were measured by Western blot in the THP-treated and control groups
Exposure of murine and human bladder cancer cells to THP resulted in elevated Akt and Erk1/2 phosphorylation in the THP group compared with the control group (Figure 1)

Summary

Introduction

Bladder cancer is one of the most frequent cancers of the urinary tract; it accounted for about 60,490 new cases and 12,240 deaths in the United States in 2017 (Siegel et al, 2017). It is reported that Akt and ERK signaling are dysregulated or mutated in human cancers, including bladder cancer (Koboldt et al, 2012; Calderaro et al, 2014; Tan et al, 2019) These genetic mutations have been validated as an essential step in the initiation and progression of human tumors. In BRAF-driven melanoma, Akt activation was observed in the clinic during vemurafenib treatment This therapy-induced activation enhances the survival of drug-sensitive cells, and acutely accelerates the expansion and dissemination of drug resistance (Mao et al, 2013). Simultaneously inhibiting both Akt and ERK pathways rather than a single pathway would be a more efficient approach to ameliorate drug response and suppress tumor growth (He et al, 2019; Yu et al, 2019)

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