The Raf/MEK/ERK pathway is frequently deregulated in cancer, thus being a key target for therapy. Although recent development of advanced inhibitors targeting B-Raf and MEK1/2 has improved therapy of B-RafV600E,K melanoma, the ability of these tumors to develop drug resistance and the intrinsic resistance of many other MEK/ERK-deregulated tumor types to these inhibitors demand additional therapeutic strategies. Because tumor cells have the ability to develop drug resistances by reactivating MEK/ERK via genetic alterations or feedback rearrangement of the associated signaling network, it is predicted that current therapeutic strategies aiming MEK/ERK inhibition will be continuously challenged. Given that, one promising strategy would be to exploit a weakness(s) of cancer cells, which is inevitably associated with their aberrant MEK/ERK activity. The goal of this project is to determine whether mortalin (GRP75/HSPA9), a molecular chaperone in the HSP70 family, can be targeted to selectively induce mitochondria-driven death mechanisms in MEK/ERK-deregulated tumor cells. In the previous funding period, we discovered that mortalin upregulation in cancer is a key mechanism that facilitates MEK/ERK-mediated tumor cell proliferative signaling by suppressing the pathway?s potential to trigger growth arrest. In an effort to further elaborate mortalin functions in cancer, we discovered that mortalin can also facilitate tumor cell survival by regulating mitochondrial bioenergetics. This latter function of mortalin needs to be thoroughly evaluated in the context of MEK/ERK signaling because the data from our preliminary studies strongly suggest that mortalin deprivation can selectively induce robust cell death in tumor cells exhibiting aberrant MEK/ERK activity, including the B-RafV600E tumor cells that have acquired resistance to B-Raf inhibitors. Moreover, our data suggest that mortalin depletion induces cell death in MEK/ERK-deregulated tumor cells by regulating adenine nucleotide translocases (ANT) and voltage-dependent anion channel (VDAC), the mitochondrial channels that are critical for cellular bioenergetics but can also turn into powerful death machinery when stressed. We therefore hypothesize that a key function of mortalin is to protect tumor cells from mitochondrial bioenergetics stress caused by aberrant MEK/ERK activity. By extension, we predict that mortalin provides a unique target to selectively trigger mitochondrial death mechanisms in MEK/ERK- deregulated tumor cells. To test these hypotheses, Aim 1 will determine whether mortalin regulates cell death/survival via ANT/VDAC-associated mitochondrial permeability transition and Ca2+ flux from ER to mitochondria.
Aim 2 will determine whether mortalin suppresses mitochondrial cell death caused by bioenergetics stress in MEK/ERK-deregulated tumor cells.
Aim 3 will determine whether mortalin targeting can effectively suppress MEK/ERK-deregulated tumors in vivo. The obtained results will help define how mortain promotes survival and proliferation of MEK/ERK-deregulated cancers.

Public Health Relevance

This project is a continuation of our research aimed at defining how mortalin facilitates proliferation and survival of MEK/ERK-deregulated cancers. We will explore new functions of mortalin that we discovered, including its ability to suppress mitochondrial cell death mechanisms and to regulate mitochondrial bioenergetics stress in MEK/ERK-deregulated cancer cells. This research is in line with the effort to develop more effective strategies to suppress MEK/ERK-deregulated tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Salnikow, Konstantin
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Medical College of Wisconsin
Schools of Medicine
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Hong, Seung-Keun; Wu, Pui-Kei; Park, Jong-In (2018) A cellular threshold for active ERK1/2 levels determines Raf/MEK/ERK-mediated growth arrest versus death responses. Cell Signal 42:11-20
Wu, Pui-Kei; Hong, Seung-Keun; Park, Jong-In (2017) Steady-State Levels of Phosphorylated Mitogen-Activated Protein Kinase Kinase 1/2 Determined by Mortalin/HSPA9 and Protein Phosphatase 1 Alpha in KRAS and BRAF Tumor Cells. Mol Cell Biol 37:
Hong, Seung-Keun; Starenki, Dmytro; Wu, Pui-Kei et al. (2017) Suppression of B-RafV600E melanoma cell survival by targeting mitochondria using triphenyl-phosphonium-conjugated nitroxide or ubiquinone. Cancer Biol Ther 18:106-114
Starenki, Dmytro; Hong, Seung-Keun; Wu, Pui-Kei et al. (2017) Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells. Cancer Biol Ther 18:473-483
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Starenki, D; Hong, S-K; Lloyd, R V et al. (2015) Mortalin (GRP75/HSPA9) upregulation promotes survival and proliferation of medullary thyroid carcinoma cells. Oncogene 34:4624-34
Wu, Pui-Kei; Park, Jong-In (2015) MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms. Semin Oncol 42:849-62
Wu, Pui-Kei; Hong, Seung-Keun; Yoon, Seung-Hee et al. (2015) Active ERK2 is sufficient to mediate growth arrest and differentiation signaling. FEBS J 282:1017-30
Starenki, Dmytro; Park, Jong In (2015) Selective Mitochondrial Uptake of MKT-077 Can Suppress Medullary Thyroid Carcinoma Cell Survival In Vitro and In Vivo. Endocrinol Metab (Seoul) 30:593-603
Karkhanis, Mansi; Park, Jong-In (2015) Sp1 regulates Raf/MEK/ERK-induced p21(CIP1) transcription in TP53-mutated cancer cells. Cell Signal 27:479-86

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