Heat shock protein 70 neutralization exerts potent antitumor effects in animal models of colon cancer and melanoma.

نویسندگان

  • Elise Schmitt
  • Loic Maingret
  • Pierre-Emmanuel Puig
  • Anne-Laure Rerole
  • François Ghiringhelli
  • Arlette Hammann
  • Eric Solary
  • Guido Kroemer
  • Carmen Garrido
چکیده

When overexpressed, the stress protein heat shock protein 70 (HSP70) increases the oncogenic potential of cancer cells in rodent models. HSP70 also prevents apoptosis, thereby increasing the survival of cells exposed to a wide range of otherwise lethal stimuli. These protective functions of HSP70 involve its interaction with and neutralization of the adaptor molecule apoptotic protease activation factor-1, implicated in caspase activation, and the flavoprotein apoptosis-inducing factor (AIF), involved in caspase-independent cell death. We have shown previously that a peptide containing the AIF sequence involved in its interaction with HSP70 (ADD70, amino acids 150-228) binds to and neutralizes HSP70 in the cytosol, thereby sensitizing cancer cells to apoptosis induced by a variety of death stimuli. Here, we show that expression of ADD70 in tumor cells decreases their tumorigenicity in syngeneic animals without affecting their growth in immunodeficient animals. ADD70 antitumorigenic effects are associated with an increase in tumor-infiltrating cytotoxic CD8+ T cells. In addition, ADD70 sensitizes rat colon cancer cells (PROb) and mouse melanoma cells (B16F10) to the chemotherapeutic agent cisplatin. ADD70 also shows an additive effect with HSP90 inhibition by 17-allylamino-17-demethoxygeldanamycin in vitro. Altogether, these data indicate the potential interest of targeting the HSP70 interaction with AIF for cancer therapy.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

The effect of interval training and consumption of Urtica dioica hydroalcoholic extract on Heat shock protein 70 and Extracellular matrix metalloproteinase inducer in C57 rats with melanoma cancer

Introduction: It has been suggested that targeted therapy of growth and immune factors may lead to more effective inhibition of tumor proliferation and recurrence in melanoma cancer. The aim of this study was to investigate the effect of interval training and consumption of Urtica dioica hydroalcoholic extract on Heat shock protein 70 (HSP70) and Extracellular matrix metalloproteinase inducer (...

متن کامل

KF25706, a novel oxime derivative of radicicol, exhibits in vivo antitumor activity via selective depletion of Hsp90 binding signaling molecules.

Radicicol, a macrocyclic antifungal antibiotic, has been shown to bind to the heat shock protein 90 (Hsp90) chaperone, interfering with its function. Hsp90 family chaperones have been shown to associate with several signaling molecules and play an essential role in signal transduction, which is important for tumor cell growth. Because radicicol lacks antitumor activity in vivo in experimental a...

متن کامل

Liposomal quercetin efficiently suppresses growth of solid tumors in murine models.

PURPOSE Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro. EXPERIMENTAL DESIGN Quercetin was encapsulate...

متن کامل

X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response

Heat shock protein 90 (HSP90) is essential for cancer cells to assist the function of various oncoproteins, and it has been recognized as a promising target in cancer therapy. Although the HSP90 inhibitors in clinical trials have shown encouraging clinical efficacy, these agents induce heat shock response (HSR), which undermines their therapeutic effects. In this report, we detailed the pharmac...

متن کامل

نقش سیستم هم اکسیژناژ بر روی رشد تومور ملانوما در موش های نژاد C57Bl6

Background and Objective: Some evidence about the relationship between heme oxygenase and many cancers is available. Heme oxygenase has anti-apoptotic effects and contributes to tumor growth. The aim of this study was to evaluate the effect of heme oxygenase on melanoma tumor cells mitosis and tumor size in C57BL/6 mice. Materials and Methods: B16F10 melanoma cells were injected subcutaneously ...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • Cancer research

دوره 66 8  شماره 

صفحات  -

تاریخ انتشار 2006