title: Loss of STK11 expression is an early event in prostate carcinogenesis and predicts therapeutic response to targeted therapy against MAPK/p38.
abstract: Prostate cancer (PCa) is the second leading cause of cancer-related death in men; however, the molecular mechanisms leading to its development and progression are not yet fully elucidated. Of note, it has been recently shown that conditional stk11 knockout mice develop atypical hyperplasia and prostate intraepithelial neoplasia (PIN). We recently reported an inverse correlation between the activity of the STK11/AMPK pathway and the MAPK/p38 cascade in HIF1A-dependent malignancies. Furthermore, MAPK/p38 overactivation was detected in benign prostate hyperplasia, PIN and PCa in mice and humans. Here we report that STK11 expression is significantly decreased in PCa compared to normal tissues. Moreover, STK11 protein levels decreased throughout prostate carcinogenesis. To gain insight into the role of STK11-MAPK/p38 activity balance in PCa, we treated PCa cell lines and primary biopsies with a well-established MAPK14-MAPK11 inhibitor (SB202190), which has been extensively used in vitro and in vivo. Our results indicate that inhibition of MAPK/p38 significantly affects PCa cell survival in an STK11-dependent manner. Indeed, we found that pharmacologic inactivation of MAPK/p38 does not affect viability of STK11-proficient PCa cells due to the triggering of the AMPK-dependent autophagic pathway, while it induces apoptosis in STK11-deficient cells irrespective of androgen receptor (AR) status. Of note, AMPK inactivation or autophagy inhibition in STK11-proficient cells sensitize SB202190-treated PCa cells to apoptosis. On the other end, reconstitution of functional STK11 in STK11-deficient PCa cells abrogates apoptosis. Collectively, our data show that STK11 is a key factor involved in the early phases of prostate carcinogenesis, and suggest that it might be used as a predictive marker of therapeutic response to MAPK/p38 inhibitors in PCa patients.
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Grossi
authors.affiliation: b Urology, Andrology and Kidney Transplantation Unit ; Department of Emergency and Organ Transplantation (DETO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lucarelli
authors.affiliation: c Cancer Genetics Laboratory; IRCCS "S. de Bellis" ; Castellana Grotte ( BA ), Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Forte
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.|d National Cancer Institute; IRCCS Oncologico Giovanni Paolo II ; Bari , Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Peserico
authors.affiliation: e Developmental Biology and Cancer; UCL Institute of Child Health ; London , UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Matrone
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Germani
authors.affiliation: b Urology, Andrology and Kidney Transplantation Unit ; Department of Emergency and Organ Transplantation (DETO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Rutigliano
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stella
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Bagnulo
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Loconte
authors.affiliation: b Urology, Andrology and Kidney Transplantation Unit ; Department of Emergency and Organ Transplantation (DETO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Galleggiante
authors.affiliation: f Department of Pathology ; University of Foggia ; Foggia , Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanguedolce
authors.affiliation: f Department of Pathology ; University of Foggia ; Foggia , Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Cagiano
authors.affiliation: f Department of Pathology ; University of Foggia ; Foggia , Italy.
authors.forename: Pantaleo
authors.initials: P
authors.lastname: Bufo
authors.affiliation: g Department of Pathology ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Senia
authors.initials: S
authors.lastname: Trabucco
authors.affiliation: g Department of Pathology ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Maiorano
authors.affiliation: b Urology, Andrology and Kidney Transplantation Unit ; Department of Emergency and Organ Transplantation (DETO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Ditonno
authors.affiliation: b Urology, Andrology and Kidney Transplantation Unit ; Department of Emergency and Organ Transplantation (DETO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.affiliation: a Division of Medical Genetics; Department of Biomedical Sciences and Human Oncology (DIMO) ; University of Bari 'Aldo Moro' ; Bari , Italy.|c Cancer Genetics Laboratory; IRCCS "S. de Bellis" ; Castellana Grotte ( BA ), Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Simone
keywords: AMPK; MAPK/p38; STK11; apoptosis; autophagy; drug resistance; prostate cancer