TY - JOUR
T1 - Oncogenic protein kinase Cι signaling mechanisms in lung cancer
T2 - Implications for improved therapeutic strategies
AU - Yin, Ning
AU - Liu, Yi
AU - Murray, Nicole R.
AU - Fields, Alan P.
N1 - Funding Information:
We acknowledge members of the Fields laboratory for their scientific input to, and critical feedback on, the manuscript. This work was supported by grants from the National Institutes of Health / National Cancer Institute ( R01 CA081436-21 and R01 CA206267-03 to APF ; R01 CA140290-05 to NRM ). APF is the Monica Flynn Jacoby Professor of Cancer Research, an endowment fund that provides partial support for the investigator's research program. NY and YL are recipients of the Edward C. Kendall Fellowship in Biochemistry from the Mayo Clinic Graduate School .
Funding Information:
We took a different approach to developing PKC? inhibitors. Specficially, we conducted a high throughput screen of FDA-approved small molecules for drugs capable of disrupting PB1-mediated binding of PKC? to PAR6 thereby identifying aPKC selective inhibitors with a unique mode of inhibition (Erdogan et al., 2006; Fields et al., 2007; Regala et al., 2008; Stallings-Mann et al., 2006). As described above, activation of PKC?-driven oncogenic signaling cascades requires binding of PKC? to the polarity protein PAR6, mediated through direct interaction of their PB1 domains (Frederick et al., 2008; Regala et al., 2005a). Due to the presence of a PB1 domain in the regulatory domain of aPKCs, but not other PKC isoforms, inhibitors identified via this screen uniquely block aPKC signal transduction via disruption of a signaling complex, rather than inhibition of catalytic activity (Erdogan et al., 2006; Stallings-Mann et al., 2006). This screen identified the gold-containing class of anti-rheumatoid drugs, aurothiomalate (ATM) and auranofin (ANF), as capable of preventing the interaction between PKC? and Par6 at concentrations achieved in clinical use as anti-rheumatoid compounds (Stallings-Mann et al., 2006). These gold compounds also blocked PKC?-mediated signal transduction in intact cells and lung cancer cell transformed growth as xenograft tumors (Stallings-Mann et al., 2006). Detailed characterization of the mechanism of action of these gold salts revealed that they form thio-gold adducts with a unique cysteine residue in the PB1 domain of PKC? (Cys-69) thereby disrupting the binding interface with PAR6 (Erdogan et al., 2006). Functionally, the Cys-69 residue of PKC? is required for inhibition of PKC? signaling and lung cancer cell transformed growth (Erdogan et al., 2006). Supporting the specificity of these compounds for PKC?, ATM-mediated inhibition of the transformed growth of NSCLC cells was blocked by expression of a Cys69Ile or Val PKC? mutant that does not bind these gold compounds (Erdogan et al., 2006). Furthermore, gold salt-mediated inhibition of transformed growth correlated positively with tumor cell expression of PKC? and PAR6, but not with expression of thioredoxin reductase 1 or 2, purported targets for ATM in rheumatoid arthritis, nor with sensitivity to cytotoxic chemotherapeutic drugs (Regala et al., 2008). These data predict that gold-containing compounds will have antitumor effects in patients with lung cancer, and possibly other cancers, and particularly those expressing high levels of PKC?. Early clinical assessment of these gold-containing compounds established a maximum tolerated dose for ATM (50?mg weekly), a dose that achieved serum gold levels at or above levels that conferred strong anti-tumor effects in preclinical models (Mansfield et al., 2013), and revealed that ANF (3?mg twice a day for 28 days) was well tolerated (Jatoi et al., 2014), supporting further clinical investigation of PKC? as a target for lung and ovarian cancer therapy. Trials of ANF in combination with mTOR inhibition are ongoing in lung and ovarian cancer patients.We acknowledge members of the Fields laboratory for their scientific input to, and critical feedback on, the manuscript. This work was supported by grants from the National Institutes of Health/National Cancer Institute (R01 CA081436-21 and R01 CA206267-03 to APF; R01 CA140290-05 to NRM). APF is the Monica Flynn Jacoby Professor of Cancer Research, an endowment fund that provides partial support for the investigator's research program. NY and YL are recipients of the Edward C. Kendall Fellowship in Biochemistry from the Mayo Clinic Graduate School.
Publisher Copyright:
© 2019
PY - 2020/1
Y1 - 2020/1
N2 - Protein Kinase Cι (PKCι) is a major oncogene involved in the initiation, maintenance and progression of numerous forms of human cancer. In the lung, PKCι is necessary for the maintenance of the transformed phenotype of the two major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC). In addition, PKCι is necessary for both LADC and LSCC tumorigenesis by establishing and maintaining a highly aggressive stem-like, tumor-initiating cell phenotype. Interestingly however, while PKCι signaling in these two major lung cancer subtypes shares some common elements, it also drives distinct, sub-type specific pathways. Furthermore, recent analysis has revealed both PKCι-dependent and PKCι-independent pathways to LADC development. Herein, we discussion our current knowledge of oncogenic PKCι signaling in LADC and LSCC, and discuss these findings in the context of how they may inform strategies for improved therapeutic intervention in these deadly diseases.
AB - Protein Kinase Cι (PKCι) is a major oncogene involved in the initiation, maintenance and progression of numerous forms of human cancer. In the lung, PKCι is necessary for the maintenance of the transformed phenotype of the two major forms of non-small cell lung cancer (NSCLC), lung adenocarcinoma (LADC) and lung squamous cell carcinoma (LSCC). In addition, PKCι is necessary for both LADC and LSCC tumorigenesis by establishing and maintaining a highly aggressive stem-like, tumor-initiating cell phenotype. Interestingly however, while PKCι signaling in these two major lung cancer subtypes shares some common elements, it also drives distinct, sub-type specific pathways. Furthermore, recent analysis has revealed both PKCι-dependent and PKCι-independent pathways to LADC development. Herein, we discussion our current knowledge of oncogenic PKCι signaling in LADC and LSCC, and discuss these findings in the context of how they may inform strategies for improved therapeutic intervention in these deadly diseases.
KW - Genetically-engineered mouse models
KW - Lung adenocarcinoma
KW - Lung squamous cell carcinoma
KW - Oncogenic signaling pathways
KW - Protein kinase Cι
UR - http://www.scopus.com/inward/record.url?scp=85073557108&partnerID=8YFLogxK
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U2 - 10.1016/j.jbior.2019.100656
DO - 10.1016/j.jbior.2019.100656
M3 - Article
C2 - 31623973
AN - SCOPUS:85073557108
SN - 2212-4926
VL - 75
JO - Advances in Biological Regulation
JF - Advances in Biological Regulation
M1 - 100656
ER -